Pharmaceutical compositions with improved dissolution

ABSTRACT

The invention relates to methods of screening mixtures containing a pharmaceutical compound and an excipient to identify properties of the pharmaceutical compound/excipient combination that retard solid-state nucleation. The invention further relates to increasing the solubility, dissolution and bioavailability of a drug with low solubility in gastric fluids conditions by combining the drug with a precipitation retardant and an optional enhancer.

RELATED APPLICATIONS

This application has been converted from U.S. Provisional ApplicationNo. 60/390,881, filed on Jun. 21, 2002 which is hereby incorporated byreference for all purposes. This application also claims priority toU.S. Provisional Application No. 60/426,275, filed on Nov. 14, 2002;U.S. Provisional Application No. 60/427,086 filed on Nov. 15, 2002; U.S.Provisional Application No. 60/429,515 filed on Nov. 26, 2002; U.S.Provisional Application No. 60/437,516 filed on Dec. 30, 2002; and U.S.Provisional Application No. 60/456,027 filed on Mar. 18, 2003 which arehereby incorporated by reference for all purposes.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions and methodsfor preparing same.

BACKGROUND OF THE INVENTION

Celecoxib(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide)is a substituted pyrazolylbenzenesulfonamide represented by thestructure (I):

Celecoxib belongs to the general class of non-steroidalanti-inflammatory drugs (NSAIDs). Unlike traditional NSAIDs, celecoxibis a selective inhibitor of cyclooxygenase II (COX-2) that causes fewerside effects when administered to a subject. The synthesis and use ofcelecoxib are further described in U.S. Pat. Nos. 5,466,823, 5,510,496,5,563,165, 5,753,688, 5,760,068, 5,972,986, 6,156,781, and 6,579,895,the contents of which are incorporated by reference in their entireties.Orally deliverable liquid formulations of celecoxib are discussed inU.S. Patent Application Publication No. 2002/0107250, the contents ofwhich are incorporated herein by reference in their entirety.

Other COX-2 inhibitory drugs are related to celecoxib, which form partof a larger group of drugs, all of which are benzene sulfonamides. Theseinclude: deracoxib, which is4-[3-fluoro-4-methoxyphenyl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide; valdecoxib, which is 4-[5-methyl-3-phenylisoxazol-4-yl]benzene sulfonamide; rofecoxib, which is3-phenyl-4-[-(methylsulfonyl)phenyl]-5H-furan-2-one; and etoricoxib,which is5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine.These drugs are described in further detail in WO 01/78724 and WO02/102376.

In its commercially available form, trademarked as CELEBREX, celecoxibis a neutral molecule that is essentially insoluble in water. Celecoxibtypically exists as needle-like crystals, which tend to aggregate into amass. Aggregation occurs even when celecoxib is mixed with othersubstances, such that a non-uniform mixture is obtained. Theseproperties are shared by other pyrazolylbenzenesulfonamides and presentsignificant problems in preparing pharmaceutical formulations of thedrugs, particularly oral formulations.

It would be advantageous to provide new forms of drugs that have lowaqueous dissolution which have improved properties, in particular asoral formulations. In particular, even where an active pharmaceuticalingredient (API) of low aqueous solubility is provided in a form whichhas improved aqueous solubility, there still exists a problem whendissolution of the API is required, for example after having been takenas an oral formulation where the API becomes diluted in the alimentarycanal. (The terms “API” and “pharmaceutical” are used hereininterchangeably.) In this situation, APIs having low aqueous solubilitytend to come out of solution. When this happens, for example by aprocess of crystallization or precipitation, the bioavailability of theAPI is significantly decreased. It would therefore be desirable toimprove the properties of formulations containing such APIs so as toincrease the bioavailability of the API in an orally-administered form,thereby providing a more rapid onset to therapeutic effect.

SUMMARY OF THE INVENTION

It has now been found that stable, crystalline salts and co-crystals ofcelecoxib can be synthesized. The celecoxib compositions of the presentinvention have a greater solubility, dissolution, total bioavailability(area under the curve or AUC), lower T_(max), the time to reach peakblood serum levels, and higher C_(max), the maximum blood serumconcentration, than neutral celecoxib. The celecoxib compositions of thepresent invention also include compounds that are less hygroscopic andmore stable. The celecoxib salts of the present invention when incrystalline form convert to either an amorphous free form of celecoxibupon neutralization of the salt, which subsequently converts to aneutral metastable crystalline form or directly to a neutral metastablecrystalline form. These amorphous and metastable crystalline forms ofneutral celecoxib are more readily available forms of the API than ispresently-marketed neutral celecoxib. Neutral crystalline celecoxib ispresently-marketed as CELEBREX, and is designated as “neutral” todistinguish it from the ionized salt form of celecoxib. In addition,acidification or neutralization of a solution of the celecoxib salt insitu yields amorphous celecoxib, which subsequently converts to ametastable crystalline form or directly to a neutral metastablecrystalline form of neutral celecoxib before finally converting intostable, neutral celecoxib.

An aspect of the present invention relates to methods of increasingdissolution, solubility, and or the time an API (either alone or as partof a pharmaceutical composition), can be maintained, upon dissolution,as a supersaturated solution, before precipitating out of solution. Theincrease in dissolution (or concentration as a function of time) resultsin, and thus can be represented by an increase in bioavailability, AUC,reduced time to T_(max) or increased C_(max). The methods comprise thesteps of making a salt or co-crystal from an API (e.g. free acid) andcombining the salt or co-crystal with a precipitation retardant andoptionally, a precipitation retardant enhancer (referred to as enhancerhereafter). The term “precipitation” refers to either a crystalline oramorphous solid form separating or “coming out of” the solution. Thesalt may be amorphous or crystalline, but is preferably crystalline.Normally the salt or co-crystal form used is in a crystalline form thatdissolves and then recrystallizes and precipitates out of solution,which is why the term “crystallization” retardant may be used in placeof “precipitation” for greater specificity. The term “crystallization”retardant can also be used to specify a salt or co-crystal that was inamorphous form prior to dissolution, and precipitates out of solution incrystalline form after dissolution. Crystalline salts are superior toamorphous salts as the initial compound, with an amorphous salt beingsuperior to a neutral amorphous or crystalline form. Free acid forms arenot preferred initial compounds unless first solubilized in asolubilizer resulting in a liquid formulation comprising a precipitationretardant and optional enhancer. The precipitation retardant is often asurfactant, preferably a surfactant with an ether functional group,preferably a repeating ether group, e.g., an ether group repeated atleast two or three times wherein the oxygen atoms are separated by 2carbon atoms. Further preferred surfactants have an interfacial tensionof less than 10 dynes per centimeter when measured at a concentration of0.1 percent w/w in water at 25 degrees C. and/or the surface tension ofthe precipitation retardant (e.g., poloxamers) is less than 42 dynes/cmwhen measured as a concentration of 0.1% w/w in water at 25 degrees C.The combination of salt or co-crystal, precipitation retardant and anoptional enhancer (or precipitation retardant, an optional enhancer andsome other form) preferably prevents or delays precipitation of asupersaturated solution by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50,55, or 60 minutes or greater than 1 hour in an aqueous solution,preferably water or gastric fluid conditions such as the gastric fluidsof an average human stomach fasted for 12 hours or simulated gastricfluid (SGF). Preferably, the solution remains supersaturated for morethan 15, 20, or 30 minutes to allow the composition to move out of thestomach and into an environment with a higher pH. The SGF may be dilutedby 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold to represent water intake. Forexample, the SGF may be diluted 5 fold to represent a patient drinking aglass of water at the time a composition of the present invention istaken orally. The degree of increase in solubility, dissolution, and/orsupersaturation may be specified, such as by 10, 20, 30, 40, 50, 60, 70,80, 90, or 100%, or by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50,75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or100,000 fold greater than neutral celecoxib (e.g., free acid) in thesame solution. The increase in dissolution may be further specified bythe time the composition remains supersaturated.

The enhancer preferably comprises a cellulose ester such ashydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).Thus according to the methods of the present invention, supersaturatedconcentrations upon which a drug may be maintained upon dissolutionand/or the degree of dissolution of a drug in gastric fluid conditions(e.g., SGF) is enhanced.

Normally, the enhancer does not improve or only minimally improves (lessthan/equal to 10%) the length of time the API can remain supersaturatedwithout the additional presence of the precipitation retardant. Themethods of the present invention are used to make a pharmaceutical drugformulation with greater solubility, dissolution, and bioavailability,AUC, reduced time to T_(max), the time to reach peak blood serum levels,and higher C_(max), the maximum blood serum concentration, when comparedto the neutral form or salt alone. AUC is the area under the plot ofplasma concentration of drug (not logarithm of the concentration)against time after drug administration. The area is convenientlydetermined by the “trapezoidal rule”: the data points are connected bystraight line segments, perpendiculars are erected from the abscissa toeach data point, and the sum of the areas of the triangles andtrapezoids so constructed is computed. When the last measuredconcentration (C_(n), at time t_(n)) is not zero, the AUC from t_(n) toinfinite time is estimated by C_(n)/k_(el).

The AUC is of particular use in estimating bioavailability of drugs, andin estimating total clearance of drugs (Cl_(T)). Following singleintravenous doses, AUC=D/Cl_(T), where D is the dose, for singlecompartment systems obeying first-order elimination kinetics;alternatively, AUC=C₀/k_(el), where k_(el) is the drug elimination rateconstant. With routes other than the intravenous, AUC=F·D/Cl_(T), whereF is the absolute bioavailability of the drug.

The invention further relates to wherein a precipitation retardant andan optional enhancer is combined with a pharmaceutical that is alreadyin a salt or co-crystal form. The invention further relates to wherein aprecipitation retardant and an optional enhancer is combined with apharmaceutical that is a solvate, desolvate, hydrate, dehydrate, oranhydrous form of a salt or co-crystal form.

Accordingly, in a further aspect, the present invention provides apharmaceutical composition comprising:

(a) an API having low aqueous solubility or dissolution, preferably ingastric fluid conditions;

(b) a precipitation retardant; and

(c) an optional enhancer.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising:

(a) an API having low aqueous solubility or dissolution, preferably ingastric fluid conditions;

(b) a precipitation retardant having an interfacial tension of less than10 dyne/cm or a surface tension of less then 42 dyne/cm; and

(c) an optional enhancer.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising:

(a) an API having low aqueous solubility or dissolution, preferably ingastric fluid conditions;

(b) a surfactant; and

(c) an optional enhancer.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising:

(a) an API having low aqueous solubility or dissolution, preferably ingastric fluid conditions;

(b) a poloxamer having an interfacial tension of less than 10 dyne/cm orsurface tension less then 42 dyne/cm; and

(c) an optional enhancer.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising:

(a) an API having low aqueous solubility or dissolution, preferably ingastric fluid conditions;

(b) a surfactant; and

(c) a cellulose ester.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising:

(a) an API having low aqueous solubility or dissolution, preferably ingastric fluid conditions;

(b) a surfactant having an interfacial tension of less than 10 dyne/cmor surface tension less then 42 dyne/cm; and

(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising:

(a) an API having low aqueous solubility or dissolution, preferably ingastric fluid conditions;

(b) a poloxamer; and

(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising:

(a) an API having low aqueous solubility or dissolution, preferably ingastric fluid conditions;

(b) a poloxamer having an interfacial tension of less than 10 dyne/cm orsurface tension less then 42 dyne/cm; and

(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising

(a) celecoxib;

(b) a poloxamer surfactant having an interfacial tension at aconcentration of 0.1% of less than 10 dyne/cm or surface tension lessthen 42 dyne/cm; and

(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).

In a further aspect, the present invention provides a process forproducing a pharmaceutical composition for delivering a supersaturatedconcentration of a drug having low aqueous dissolution, preferably ingastric fluid conditions, which comprises intimately mixing together thecomponents of the above aspects or elsewhere herein.

In a further aspect, the surfactant is at a concentration of less than5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or0.1% or at a concentration of 0.1% (w/w) upon dissolving in thedissolution medium.

The present invention further provides a process for producing apharmaceutical composition, which comprises:

-   -   (1) providing a plurality of containers;    -   (2) providing a plurality of excipient solutions;    -   (3) providing a plurality of compound solutions, each having        dissolved therein a pharmaceutical compound;    -   (4) dispensing into each container one of the excipient        solutions with one of the compound solutions so as to form an        intimate mixture, a property of each mixture being varied in        different containers;    -   (5) incubating the mixture;    -   (6) determining onset of solid-state nucleation or        precipitation;    -   (7) selecting a pharmaceutical compound/excipient combination        whereby onset of solid-state nucleation is retarded; and    -   (8) producing a pharmaceutical composition comprising the        pharmaceutical compound/excipient combination.

Applicants found that it is possible to screen mixtures containing apharmaceutical compound and an excipient in a rapid and simple manner soas to identify which properties of the pharmaceutical compound/excipientcombination retard (inhibit) solid-state nucleation. The term“solid-state nucleation” is used herein to refer to the initiation ofsolidification, whether amorphous or crystalline, but may be specifiedas being amorphous or crystalline. In this way, those excipients orother properties of the combination can be chosen for the production ofa pharmaceutical composition in which the API remains in solution for asufficient time after administration to a subject. In this way,pharmaceutical compositions which attain at least a minimumbioavailability of the API may be readily produced based on astraightforward in vitro screen.

Various properties of a pharmaceutical composition may affect the onsetof solid-state nucleation or precipitation of the API. Such propertiesinclude the identity or amount of the excipient and the identity oramount of the pharmaceutical compound in the composition. Otherproperties may include the amount of other diluents or carriers such assalts or buffering compounds. The pharmaceutical compound itself may bescreened in a variety of different forms if it is capable ofpolymorphism. Additionally, different salt, solvate, hydrate, co-crystaland other forms of the API may be screened in accordance with theinvention.

The invention is readily applicable to screening a large variety ofdifferent excipients. Accordingly, in a preferred aspect, the presentinvention provides a process for producing a pharmaceutical composition,which comprises:

-   -   (1) providing a plurality of containers;    -   (2) providing a plurality of excipient solutions;    -   (3) providing a plurality of compound solutions, each having        dissolved therein a pharmaceutical compound;    -   (4) dispensing into each container one of the excipient        solutions with one of the compound solutions so as to form an        intimate mixture, the excipient being varied in different        containers;    -   (5) incubating the mixture;    -   (6) determining onset of solid-state nucleation or        precipitation;    -   (7) selecting an excipient which is found to retard onset of        solid-state nucleation or precipitation; and    -   (8) producing a pharmaceutical composition comprising the        pharmaceutical compound and the selected excipient.

According to this embodiment, it is the excipient which is varied.Different excipients may be used in different containers and may bepresent as a single excipient or in a combination of a plurality ofexcipients, for example, a binary, ternary, tertiary or higher ordercombination.

In a further aspect, the present invention provides a pharmaceuticalcomposition obtained by processes according to the invention. Thepharmaceutical composition may comprise a further excipient, diluent orcarrier. In a preferred aspect, the pharmaceutical composition isformulated for oral administration.

The invention further provides a method for assessing excipient-mediatedretardation of solid-state nucleation or precipitation of apharmaceutical compound, which method comprises:

-   -   (1) providing a plurality of containers;    -   (2) providing a plurality of excipient solutions;    -   (3) providing a plurality of compound solutions, each having        dissolved therein a pharmaceutical compound;    -   (4) dispensing into each container one of the excipient        solutions with one of the compound solutions so as to form an        intimate mixture, a property of each mixture being varied in        different containers;    -   (5) incubating the mixture;    -   (6) determining onset of solid-state nucleation or        precipitation; and    -   (7) ranking the property of the mixture according to time of        onset of solid-state nucleation or precipitation.

In a further aspect the present invention provides a method forscreening excipients that retard solid-state nucleation or precipitationof a pharmaceutical compound, which method comprises:

-   -   (1) providing a plurality of containers;    -   (2) providing a plurality of excipient solutions;    -   (3) providing a plurality of compound solutions, each having        dissolved therein a pharmaceutical compound;    -   (4) dispensing into each container one of the excipient        solutions with one of the compound solutions so as to form an        intimate mixture, the excipient being varied in different        containers;    -   (5) incubating the mixture;    -   (6) determining onset of solid-state nucleation or        precipitation; and    -   (7) ranking the excipient according to time of onset of        solid-state nucleation or precipitation.

Generally speaking, the active pharmaceutical ingredient (API) istypically capable of existing as a supersaturated solution, preferablyin an aqueous-based medium. The API may be a free acid, free base,co-crystal or salt, or a solvate, hydrate or dehydrate thereof. Theinvention is particularly applicable to pharmaceutical compositionscomprising an API which, when in contact with a body fluid such asgastric juices or intestinal fluids, would be likely to precipitate orcrystallize from solution in a nucleation event. Accordingly, theinvention is particularly applicable to pharmaceutical compounds whichmay have relatively low solubility, or dissolution, as defined herein,when in contact with bodily fluids but possibly relatively highsolubility, or dissolution, in appropriate in vitro conditions.

According to the invention, the compound solution is a solution whereinthe compound is solubilized and may be a non-aqueous solution or anaqueous solution with a pH adjusted to accommodate the compound. Forexample, in order to achieve high solubility of the compound, a freebase-type compound would be dissolved in aqueous solution at acidic pHwhereas a free acid-type compound would be dissolved in an aqueoussolution of basic pH. The compound solution may therefore be, andpreferably is, a supersaturated solution when compared to water, gastricfluids or intestinal fluids. It would also be preferred for theexcipient to be in a solution comprising water, usually deionised water,or another aqueous based solution. In one aspect, the mixture simulatesgastric fluid (SGF) or intestinal fluids (SIF, 0.68% monobasic potassiumphosphate, 1% pancreatin, and sodium hydroxide where the pH of the finalsolution is 7.5.) and in this aspect it is preferred that the excipientis added in a solution simulating those body fluids. Alternatively,further additives, usually in solution, may be added to form themixtures creating an environment appropriate for the screening to beundertaken.

One advantage of the present invention is that the plurality ofcontainers may be presented in a multiple well plate format or block andtube format such that at least 24, 48, 96, 384, or 1536 samples areassayed in parallel. Multiple block and tubes or multiwell plates may beassayed such that at least 1000, 3000, 5000, 7000, 10000, 20000, 30000,40000, 50000, 60000, 70000, 80000, 90000, or 100000 total samples areassayed. This is advantageous because the process may be operated in asemi-automated or automated way using existing multiple well plateformat-based apparatus. At least the step of dispensing may be performedwith automated liquid handling apparatus. Accordingly, it is possible tooperate the process as a high throughput screen. Additionally, using amultiple well plate format, the scale of the screening is relativelylow. For example, each sample may contain less than 100 mg, 50 mg, 25mg, 10, mg, 5 mg, 750 micrograms, 500 micrograms, 250, micrograms, 100micrograms, 75 micrograms, 50 micrograms, 25 micrograms, 10 micrograms,1 microgram, 750 ng, 500 ng, 250 ng, 100 ng, or less than 50 ng,depending on the API, sample size, etc. This, therefore, minimizes theamount of API which is needed to identify excipients or properties ofthe combination of pharmaceutical compound and excipient that retardonset of nucleation. In this way, improved speed and relatively low costare advantages.

The intimate mixture formed in the process may be achieved by anyconventional method, including the use of a mixer during or afterdispensing of the solutions. Once the mixture has been formed, it isgenerally advantageous to incubate the mixture at a constanttemperature, such as approximately 37 degrees C., to simulate in vivoconditions.

Measurement of onset of solid-state nucleation or precipitation may bedetermined for example, by measuring the light scattering of a mixture.This may be achieved by any conventional light scattering measurement,such as the use of a nephelometer. It is also possible to include afurther step in which the crystallinity of the products of thesolid-state nucleation or precipitation is determined. This step isconveniently performed before selecting the pharmaceuticalcompound/excipient combination for use in the pharmaceuticalcomposition. Crystallinity may be determined, e.g., by birefringencescreening.

Neither the light scattering measurement nor the birefringence screeningare invasive measurement techniques. Advantageously, a portion or all ofthe sample solution does not need to be transferred to a secondcontainer and the containers or wells can be sealed with a transparentseal to allow use of these techniques.

In its most general aspect, the present invention relates to apharmaceutical composition which includes an API having a low aqueoussolubility or dissolution (as defined herein). Typically, low aqueoussolubility in the present application refers to a compound having asolubility in water which is less than or equal to 10 mg/mL, whenmeasured at 37 degrees C., and preferably less than or equal to 1 mg/mL.The invention relates more particularly to drugs which have a solubilityof not greater than 0.1 mg/mL. The invention further relates tocompounds that cannot be maintained as a supersaturated solution ingastric or intestinal fluid or in SGF or SIF. Such drugs include somesulfonamide drugs, such as the benzene sulfonamides, particularly thosepyrazolylbenzenesulfonamides discussed above, which include COX-2inhibitors. Disclosed herein are stable crystalline metal salts ofpyrazolylbenzenesulfonamides such as celecoxib. Such metal salts includealkali metal or alkaline earth metal salts, preferably sodium,potassium, lithium, calcium and magnesium salts.

It is preferred that the pharmaceutical composition is formulated fororal administration. Drugs according to the invention may be prepared ina form having reduced time to onset of therapeutic effectiveness (thetime when an effect for which the drug is administered can be identifiedor measured, e.g., the point in time when a reduction in fever or painfelt by a patient begins to occur) or increased bioavailability. Thepharmaceutical compositions according to the invention are thereforeparticularly suitable for administration to human subjects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a reproduction of a differential scanning calorimetry (DSC)thermogram of the sodium salt of celecoxib prepared by Example 1 between50 degrees C. and 110 degrees C.

FIG. 2 shows a reproduction of a thermogravimetric analysis (TGA)thermogram of the sodium salt of celecoxib prepared by Example 1, whichwas conducted from about 30 degrees C. to about 160 degrees C.

FIG. 3 shows a reproduction of a PXRD diffractogram of the sodium saltof celecoxib prepared by Example 1.

FIGS. 4A and 4B show pharmacokinetics in male Sprague-Dawley rats after5 mg/kg oral doses of the celecoxib crystal form used in the marketedformulations and the sodium salt of4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,as obtained following the protocol described in Example 4.

FIGS. 5A and 5B show the formulations and mean pharmacokineticparameters (and standard deviations thereof) of celecoxib in the plasmaof male dogs following a single oral or single intravenous dose ofcelecoxib or celecoxib sodium salt.

FIG. 5C shows a linear dose response with a plot of AUC versus dose.

FIG. 6 shows the mean concentrations of celecoxib in plasma followingthe administration of a single oral dose of celecoxib or celecoxibsodium or a single intravenous dose of celecoxib in male dogs.

FIG. 7 shows the effect of varying ratios of ethylene glycol topropylene glycol subunits in poloxamers on the concentration ofcelecoxib sodium salt in solution.

FIG. 8 shows the effect of different celluloses on the dissolution ofvarious compositions comprising equal weights of cellulose(hydroxypropylcellulose (HPC, 100,000 kDa), low-viscosityhydroxypropylmethylcellulose (low-density HPMC, viscosity 80-120 cps),high-viscosity hydroxypropylmethylcellulose (high-density HPMC,viscosity 15,000 cps), or microcrystalline cellulose (Avicel PH200)), ind-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TPGS)and celecoxib sodium.

FIG. 9 shows the dissolution at 37 degrees C. for compositionscomprising various weight ratios of d-alpha-tocopherol polyethyleneglycol-1000 succinate (vitarnin E TGPS), hydroxypropylcellulose, andcelecoxib sodium salt.

FIG. 10 shows the dissolution profile of celecoxib sodium salt insimulated gastric fluid (SGF) from solid mixtures with excipients atroom temperature. The legend indicates the excipient and the weightratio of excipient to celecoxib sodium (if unmarked, 1:1). Excipientsinclude polyvinylpyrrolidone (PVP), poloxamer 188 (P188), poloxamer 237(P237), d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin ETPGS), and Gelucire™ 50/13.

FIG. 11 shows the effect of Avicel microcrystalline cellulose and silicagel on the dissolution of mixtures of celecoxib sodium salt,d-alpha-tocopherol polyethylene glycol-1000 succinate (vit E TGPS), andhydroxypropylcellulose (HPC) mixtures in simulated gastric fluid (SGF)at 37 degrees C. The legend indicates the weight ratios of thecomponents.

FIG. 12 shows the dissolution of celecoxib sodium salt in 5-timesdiluted simulated gastric fluid, with excipients includingd-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TPGS),hydroxypropylcellulose (HPC), and poloxamer 237. The legend indicatesthe weight ratios of the components.

FIGS. 13A and 13B show the PXRD diffractogram and Raman spectrum,respectively, of the sodium salt of celecoxib prepared by the method ofExample 6.

FIG. 14 shows a differential scanning calorimetry (DSC) thermogram ofcelecoxib lithium salt MO-116-49B.

FIG. 15 shows a thermogravimetric analysis (TGA) thermogram of celecoxiblithium salt MO-116-49B.

FIG. 16 shows the RAMAN spectrum of celecoxib lithium salt MO-116-49B.

FIG. 17 shows the PXRD diffractogram of celecoxib lithium saltMO-116-49B.

FIG. 18 shows a differential scanning calorimetry (DSC) thermogram ofcelecoxib potassium salt MO-116-49A.

FIG. 19 shows a thermogravimetric analysis (TGA) thermogram of celecoxibpotassium salt MO-116-49A.

FIG. 20 shows the RAMAN spectrum of celecoxib potassium salt MO-116-49A.

FIG. 21 shows the PXRD diffractogram of celecoxib potassium saltMO-116-49A.

FIG. 22 shows a thermogravimetric analysis (TGA) thermogram of celecoxibpotassium salt MO-116-55D.

FIG. 23 shows the RAMAN spectrum of celecoxib potassium salt MO-116-55D.

FIG. 24 shows the PXRD diffractogram of celecoxib potassium saltMO-116-55D.

FIG. 25 shows a thermogravimetric analysis (TGA) thermogram of celecoxibcalcium salt MO-116-62A.

FIG. 26 shows the RAMAN spectrum of celecoxib calcium salt MO-116-62A.

FIG. 27 shows the PXRD diffractogram of celecoxib calcium saltMO-116-62A.

FIG. 28 shows the PXRD diffractogram of commercially-availablecelecoxib.

FIG. 29 shows the RAMAN spectrum of commercially-available celecoxib.

FIG. 30 shows crystal retardation time for celecoxib as a function ofexcipient in simulated gastric fluid (SGF).

FIG. 31A shows interfacial tension of selected PLURONIC excipients inwater.

FIG. 31B shows that Pluronic concentrations greater than or equal to theCMC are preferred for effective precipitation inhibition.

FIG. 32 shows dissolution of celecoxib sodium hydrate from compositionscontaining PLURONIC P123 and F127.

FIG. 33 shows dissolution of celecoxib sodium hydrate from PLURONICP123, F127 and F87, in the presence of HPC.

FIG. 34 shows dissolution of celecoxib sodium hydrate using PLURONICF127, HPC and a granulating fluid.

FIG. 35A shows dissolution of celecoxib sodium hydrate using PLURONICF127 and HPC in a compact formulation.

FIG. 35B shows a dissolution profile of springs with and withoutparachutes.

FIG. 36 shows a flowchart outlining a process according to theinvention.

FIG. 37 shows a platemap for an automated liquid dispenser.

FIG. 38 shows a trace of light scatter against time in an assayaccording to the invention.

FIG. 39 shows a thermogravimetric analysis (TGA) thermogram of apropylene glycol solvate of a celecoxib sodium salt.

FIGS. 40A-D show the PXRD diffractograms of a propylene glycol solvateof a celecoxib sodium salt.

FIG. 41 shows a thermogravimetric analysis (TGA) thermogram of apropylene glycol solvate of a celecoxib potassium salt.

FIG. 42 shows the PXRD diffractogram of a propylene glycol solvate of acelecoxib potassium salt.

FIG. 43 shows a thermogravimetric analysis (TGA) thermogram of apropylene glycol solvate of a celecoxib lithium salt.

FIG. 44 shows a thermogravimetric analysis (TGA) thermogram of thesodium salt propylene glycol trihydrate of celecoxib prepared by Example21.

FIG. 45 shows a PXRD diffractogram of the sodium salt propylene glycoltrihydrate of celecoxib prepared by Example 21.

FIG. 46 shows a thermogravimetric analysis (TGA) thermogram of thesodium salt propylene glycoltrihydrate of celecoxib prepared by Example21.

FIG. 47 shows a PXRD diffractogram of the sodium salt propylene glycoltrihydrate of celecoxib prepared by Example 21.

FIG. 48 shows a differential scanning calorimetry (DSC) thermogram ofthe sodium salt isopropyl alcohol solvate of celecoxib prepared byExample 22.

FIG. 49 shows a thermogravimetric analysis (TGA) thermogram of thesodium salt isopropyl alcohol solvate of celecoxib prepared by Example22, which was conducted from about 30° to about 160 degrees C.

FIG. 50 shows a PXRD diffractogram of the isopropyl alcohol solvate ofcelecoxib sodium salt prepared by Example 22.

FIG. 51 shows a PXRD diffractogram of the propylene glycol solvate ofcelecoxib lithium salt prepared by Example 20.

FIG. 52 shows a PXRD diffractogram of the celecoxib:nicotinamideco-crystals prepared by Example 23.

FIG. 53 shows a PXRD diffractogram of the hydrate of celecoxib sodiumsalt under 17% RH prepared by Example 24.

FIG. 54 shows a PXRD diffractogram of the hydrate of celecoxib sodiumsalt under 31% RH prepared by Example 24.

FIG. 55 shows a PXRD diffractogram of the hydrate of celecoxib sodiumsalt under 59% RH prepared by Example 24.

FIG. 56 shows a PXRD diffractogram of the hydrate of celecoxib sodiumsalt under 74% RH prepared by Example 24.

FIG. 57 shows a PXRD diffractogram of the hydrate of the propyleneglycol solvate of celecoxib sodium salt under 17% RH prepared by Example24.

FIG. 58 shows a PXRD diffractogram of the hydrate of the propyleneglycol solvate of celecoxib sodium salt under 31% RH prepared by Example24.

FIG. 59 shows a PXRD diffractogram of the hydrate of the propyleneglycol solvate of celecoxib sodium salt under 59% RH prepared by Example24.

FIG. 60 shows a PXRD diffractogram of the hydrate of the propyleneglycol solvate of celecoxib sodium salt under 74% RH prepared by Example24.

FIG. 61 shows PXRD diffractograms of multiple celecoxib sodium saltsamples with various hydration states prepared by Example 25.

FIG. 62 shows a PXRD diffractogram of celecoxib sodium salt prepared byExample 2.

FIG. 63 shows a TGA thermogram of celecoxib potassium salt hydrate.

FIG. 64 shows a PXRD diffractogram of celecoxib potassium salt hydrate.

FIG. 65 shows a TGA thermogram of celecoxib sodium salt prepared withsodium chloride.

FIG. 66 shows a PXRD diffractogram of celecoxib sodium salt preparedwith sodium chloride.

FIG. 67 shows a dissolution profile of celecoxib sodium salt hydrate.

FIG. 68 shows in vitro dissolution data of a controlled releaseformulation of celecoxib.

FIG. 69 shows changes in the PXRD diffractogram of celecoxib sodiumhydrate as the ambient relative humidity is changed.

FIG. 70 shows changes in the PXRD diffractogram of celecoxib sodiumpropylene glycol solvate as the ambient relative humidity is changed.

FIG. 71 shows dynamic vapor sorption data of celecoxib sodium hydrate.

FIGS. 72A-B show dynamic vapor sorption data of celecoxib potassium saltand PXRD data.

FIG. 73 shows dynamic vapor sorption data of celecoxib sodium propyleneglycol solvate.

FIG. 74 shows dynamic vapor sorption data of celecoxib sodium propyleneglycol solvate.

FIG. 75 shows a comparison of PXRD diffractograms of celecoxib sodiumpropylene glycol solvate.

FIG. 76 shows dynamic vapor sorption data of celecoxib potassiumpropylene glycol solvate.

FIG. 77 shows a PXRD diffractogram of celecoxib potassium propyleneglycol solvate.

FIG. 78 shows dynamic vapor sorption data of celecoxib lithium propyleneglycol solvate.

FIG. 79 shows a comparison of PXRD diffractograms of celecoxib lithiumpropylene glycol solvate.

FIG. 80 shows dynamic vapor sorption data of a celecoxib:nicotinamideco-crystal.

FIG. 81 shows a DSC thermogram of amorphous celecoxib potassium salt.

FIG. 82 shows a Raman spectrum of amorphous celecoxib potassium salt.

FIG. 83 shows a PXRD diffractogram of amorphous celecoxib potassiumsalt.

FIG. 84 shows a TGA thermogram of a celecoxib: 18-crown-6 co-crystal.

FIG. 85 shows a DSC thermogram of a celecoxib: 18-crown-6 co-crystal.

FIG. 86 shows a PXRD diffractogram of a celecoxib: 18-crown-6co-crystal.

FIG. 87 shows a TGA thermogram of celecoxib 15-crown-5 solvate.

FIG. 88 shows a DSC thermogram of celecoxib 15-crown-5 solvate.

FIG. 89 shows a PXRD diffractogram of celecoxib 15-crown-5 solvate.

FIG. 90 shows a TGA thermogram of celecoxib diglyme solvate.

FIG. 91 shows a DSC thermogram of celecoxib diglyme solvate.

FIG. 92 shows a PXRD diffractogram of celecoxib diglyme solvate.

FIG. 93 shows a TGA thermogram of a valdecoxib: 18-crown-6 co-crystal.

FIG. 94 shows a PXRD diffractogram of a valdecoxib: 18-crown-6co-crystal.

FIG. 95 shows a single-crystal packing diagram for valdecoxib:18-crown-6 co-crystal.

FIG. 96 shows a TGA thermogram of celecoxib NMP solvate.

FIG. 97 shows a Raman spectrum of celecoxib NMP solvate.

FIG. 98 shows a PXRD diffractogram of celecoxib NMP solvate.

FIG. 99 shows a packing diagram for celecoxib NMP solvate at 100 K.

FIG. 100 shows a packing diagram for celecoxib NMP solvate at 571 K

FIG. 101 shows a TGA thermogram of celecoxib sodium salt synthesizedfrom 2-propanol.

FIG. 102 shows a DSC thermogram of celecoxib sodium salt synthesizedfrom 2-propanol.

DETAILED DESCRIPTION OF THE INVENTION

In its most general aspect, the present invention relates to apharmaceutical composition that includes an API having a low aqueoussolubility, e.g., in gastric fluid conditions. Typically, low aqueoussolubility in the present application refers to a compound having asolubility in water which is less than or equal to 10 mg/mL, whenmeasured at 37 degrees C., and preferably less than or equal to 5 mg/mLor 1 mg/mL. “Low aqueous solubility” can further be defined as less thanor equal to 900, 800, 700, 600, 500, 400, 300, 200 150 100, 90, 80, 70,60, 50, 40, 30, 20 micrograms/mL, or further 10, 5 or 1 micrograms/mL,or further 900, 800, 700, 600, 500,400, 300, 200 150, 100 90, 80, 70,60, 50, 40, 30, 20, or 10 ng/mL, or less than 10 ng/mL when measured at37 degrees C. Further aqueous solubility can be measured in simulatedgastric fluid (SGF) rather than water. SGF (non-diluted) of the presentinvention is made by combining 1 g/L Triton X-100 and 2 g/L NaCl inwater and adjusting the pH with 20 mM HCl to obtain a solution with afinal pH=1.7. The pH of the solution may also be specified as 1, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5,11, 11.5, or 12.

APIs which have a solubility of not greater than 0.1 mg/mL, includingsome sulfonamide drugs, such as the benzene sulfonamides, particularlythose pyrazolylbenzenesulfonamides discussed above, which include COX-2inhibitors, are included in the present invention. Disclosed herein arestable crystalline metal salts and co-crystals ofpyrazolylbenzenesulfonamides such as celecoxib. Such metal salts includealkali metal or alkaline earth metal salts, preferably sodium,potassium, lithium, calcium and magnesium salts.

In one aspect of the present invention, an API with low aqueoussolubility is formulated with a precipitation retardant and, optionally,with a precipitation retardant enhancer. The precipitation retardantused in the present invention can be chosen from a wide range ofsurfactants (see e.g., FIG. 30). Embodiments include where thesurfactant is non-ionic or wherein the surfactant is ionic. Inembodiments of the present invention, the interfacial tension of theprecipitation retardant (e.g., poloxamers) is less than 10 dyne/cm whenmeasured as a concentration of 0.1 percent w/w in water as compared tomineral oil at 25 degrees C. and/or the surface tension of theprecipitation retardant (e.g., poloxamers) is less than 42 dyne/cm whenmeasured as a concentration of 0.1% w/w in water. In other embodimentsof the invention the interfacial tension is less than 15, 14, 13, 12,11, 9, 8, 7, or 6 dyne/cm or the surface tension is less than 45, 44,43, 41, 40, 39, 38, 37, 36, or 35 dyne/cm. In other embodiments, thesurfactant is a poloxamer. A poloxamer comprises an ethyleneoxide-propylene oxide block copolymer, which preferably has thestructure (PEG)_(x)-(PPG)_(y)-(PEG)_(z). where x, y and z are integersand x is usually equal to z. Preferred forms of poloxamers are thoseobtainable from BASF, as trademarked PLURONIC. The invention is not,however, limited to the PLURONIC series as similar poloxamers obtainablefrom other sources may be used. Examples of PLURONIC poloxamersaccording to the invention include PLURONIC L122, PLURONIC P123,PLURONIC F127 (Poloxamer 407), PLURONIC L72, PLURONIC P105, PLURONICLP2, PLURONIC P104, PLURONIC F108 (Poloxamer 338), PLURONIC P103,PLURONIC L44 (Polaxamer 124), PLURONIC F68 (Poloxamer 188), and PLURONICF87 (Poloxamer 237). A specific poloxamer and its correspondingPLURONIC, i.e., the generic and tradename, may be used interchangeablythroughout.

In one embodiment, the invention provides a pharmaceutical compositioncomprising:

-   -   (a) an API; and    -   (b) a polyether block copolymer comprising an A-type linear        polymeric segment joined at one end to a B-type linear polymeric        segment, wherein the A-type segment is of relatively hydrophilic        character, the repeating units of which contribute an average        Hansch-Leo fragmental constant of about −0.4 or less and have        molecular weight contributions between about 30 and about 500,        wherein the B-type segment is of relatively hydrophobic        character, the repeating units of which contribute an average        Hansch-Leo fragmental constant of about −0.4 or more and have        molecular weight contributions between about 30 and about 500,        wherein at least about 80% of the linkages joining the repeating        units for each of the polymeric segments comprise an ether        linkage. In a preferred first embodiment, the polyether block        copolymer is selected from the group consisting of polymers of        formulas:        A-B-A′,   (i)        A-B,   (ii)        B-A-B′,   (iii)        or        L(R¹)(R²)(R³)(R⁴)   (iv)        wherein A and A′ are A-type linear polymeric segments, B and B′        are B-type linear polymeric segments, and R¹, R², R³ and R⁴ are        either block copolymers of formulas (i), (ii) or (iii) or        hydrogen and L is a linking group, with the proviso that no more        than two of R¹, R², R³ or R⁴ are hydrogen.

In another embodiment, the composition includes micelles of the blockcopolymer or forms micelles of the block copolymers during the course ofadministration or subsequent thereto. Preferably, at least about 0.1% ofthe API is incorporated in the micelles, more preferably, at least about1% of the API, yet more preferably, at least about 5% of the API.

In another embodiment, the hydrophobic percentage of the copolymer ofthe composition is at least about 50% more preferably, at least about60%, yet more preferably 70%.

In another embodiment, the hydrophobic weight of the copolymer is atleast about 900, more preferably, at least about 1700, yet morepreferably at least about 2000, still more preferably at least about2300.

In other embodiments, the hydrophobic weight is at least about 2000 andthe hydrophobic percentage is at least about 20%, preferably 35%; or thehydrophobic weight is at least about 2300 and the hydrophobic percentageis at least about 20%, preferably 35%.

The optional third component of the pharmaceutical composition accordingto the present invention comprises a precipitation retardant enhancer.An enhancer is a compound capable of increasing the effectiveness of theprecipitation retardant in inhibiting, preventing or at least reducingthe extent of precipitation of a drug of low aqueous solubility, usuallywhen diluted such as following oral administration. In one embodimentthe enhancer does not act as a precipitation retardant alone. In anotherembodiment the enhancer has no effect or a negative effect in an invitro precipitation assay, but increases the effectiveness of theprecipitation retardant in an in vivo or in vitro dissolution assay.Cellulose esters, such as hydroxypropyl cellulose, are particularlyuseful enhancers according to the present invention. Cellulose estersvary in the chain length of their cellulosic backbone and consequently,vary in their viscosities as measured for example at a 2% by weightconcentration in water at 20 degrees C. Lower viscosities are normallypreferred to higher viscosities in the present invention. In embodimentsof the present invention the cellulose ester, such as HPC, has aviscosity, 2% in water, of about 100 to about 100,000 cP or about 1000to about 15,000 cP. In other embodiments the viscosity is less than1,500,000, 1,000,000, 500,000, 100,000, 75,000, 50,000, 35,000, 25,000,20,000, 17,500, 15,000, 12,500. 11,000, 10,500, 9,000, 8,000, 7,000,6,000, 5,000, 4,000, 3,000, 2,000, 1,000, 750, 500, or 250 cP, or has aviscosity in a range selected from any two preceding integers.

Enhancers are also useful in delaying the T_(max) and/or increasing theamount of time the API concentration is above ½ T_(max), thus acting tosmooth out a curve of blood serum concentration vs. time. Preferredenhancers increase the amount of time the API concentration is above ½T_(max) by 25%, 50%, 75%, 100%, three fold or more than three fold. In apreferred embodiment, the composition has both a reduced time to T_(max)and remains at ½ T_(max) longer than the free acid or in the samecomposition except the salt or co-crystal is replaced by the free acid.

The ratio of component a:b:c (API: precipitation retardant;enhancer) asexemplified herein is approximately 1:1:1 (±0.2 for the precipitationretardant and enhancer). However, the ratio can be adjusted to suit theapplication. For example, the amount of precipitation retardant orenhancer may need to be decreased, and even decreased below the optimumconcentration in order to decrease the amount of excipients in theadministered form of the composition, such as a tablet or capsule. Inone embodiment the unit dosage form comprises an amount of precipitationretardant (surfactant) that is at or above an amount needed for theretardant to reach its critical micelle concentration (CMC) in H₂O orSGF. It is noted the poloxamers may not form true micells but do formanalogous structures which are considered micelles for the purpose ofthe present invention.

The composition may further comprise a pharmaceutically-acceptablediluent, excipient or carrier and such additional components arediscussed in further detail below.

One such additional component comprises a granulating fluid-like liquid,such as poloxamer 124, PEG 200 or PEG 400, that forms an intimatecontact between the API, precipitation retardant and optional enhancerby binding or partially dissolving them. Preferably the compositionremains in a solid, semi-solid or paste, although an embodiment is drawnto wherein the composition is at least 25%, 50%, 75% or nearly or fullydissolved. Any pharmaceutically acceptable liquid may be used as long asit does not cause conversion of the salt or co-crystal form to the freeform in the solid state. Some non-limiting examples include methanol,ethanol, isopropanol, higher alcohols, propylene glycol, ethylcaprylate, propylene glycol laurate, PEG, diethyl glycol monoethyl ether(DGME), tetraethylene glycol dimethyl ether, triethylene glycolmonoethyl ether, and polysorbate 80. The presence of the granulatingfluid-like liquid increases the dissolution of the API, possibly bydelaying the contact between the API and the dissolution medium untilthe surfactant dissolves to a significant extent, thus delayingprecipitation. The use of a granulating fluid-like liquid isparticularly useful when the API and precipitation retardant are solids.

As an alternative embodiment to increase supersaturation of the API, thepharmaceutical composition is in the form of a compact whereby, duringthe process of producing the pharmaceutical composition, the componentsare compacted together. Compaction may perform a similar role to thatperformed by the granulating fluid. Retarded dissolution or a smoothingout of the curve of blood serum concentration vs. time may be limited,if required, by using a disintegrant in the compact.

In a further embodiment the API and precipitation retardant (andoptional enhancer), forms a paste or non-aqueous solution when mixed. Anadherent mass of components may be produced if a paste is used, which isthought to delay dissolution of the API by allowing the surfactant todissolve first. This is thought to promote supersaturation of the API.

Normally the compounds of the present invention are intimatelyassociated as a pharmaceutical composition. An “intimate association” inthe present context includes, for example, the pharmaceutical admixedwith the precipitation retardant, the pharmaceutical embedded orincorporated in the retardant, the compound forming a coating onparticles of the pharmaceutical or vice versa, and a substantiallyhomogeneous dispersion of the pharmaceutical throughout the compounds.

Where the pharmaceutical composition includes a COX-2 inhibitor, amethod of treating a subject is provided in a further aspect of theinvention, in which the subject may be suffering from pain,inflammation, cancer or pre-cancer such as intestinal or colonic polyps.The method comprises administering to the subject a pharmaceuticalcomposition as described herein.

It is preferred that the pharmaceutical composition is formulated fororal administration. Drugs according to the invention may be prepared ina form having a decreased time to onset of therapeutic effectiveness andan increased bioavailability. The pharmaceutical compositions accordingto the invention are particularly suitable for administration to humansubjects.

The methods and compositions of the present invention relate toimproving solubility, dissolution and bioavailability ofpharmaceuticals. The present invention further relates to improving theperformance of pharmaceutical compounds that initially dissolve but thenprecipitate or recrystallize in gastric fluid conditions.

Further embodiments relate to pharmaceuticals with an aminosulfonylfunctional group. The term “aminosulfonyl functional group” hereinrefers to a functional group having the following structure (II):

Wherein the wavy line represents a bond by which the functional group isattached to the rest of the drug molecule; and R is hydrogen or asubstituent that preserves ability of polyethylene glycol or apolyethylene glycol degradation product to react with the amino groupadjacent to R to form an addition compound. Illustrative examples ofsuch substituents include partially unsaturated hereocyclyl, hereoaryl,cycloalkenyl, aryl, alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo,cyano, nitro, carboxyl, phenyl, alkoxy, aminocarbonyl, alkoxycarbonyl,carboxyalkyl, cyanoalkyl, hydroxyalkyl, hydroxyl, alkoxyalkyloxyalkyl,haloalkylsulfonyloxy, carboxyalkoxyalkyl, cycloalkylalkyl, alkynyl,heterocyclyloxy, alkylthio, cycloalkyl, heterocyclyl, cycloalkenyl,aralkyl, heterocyclylalkyl, heteroarylcarbonyl, alkylthioalkyl,arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl,aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl,N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-Narylamino,aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylamincoalkyl,N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,aralkoxy, arylthio, aralkylthio, alkylsufinyl, alkylsufonyl, etc.

Non-limiting illustrative examples of aminosulfonyl-comprising drugsinclude ABT-751 of Eisai(N-(2-(4-hydroxyphenyl)amino)-3-pyridyl)4-methoxybenzenesulfonamide);alpiropride; amosulalol; amprenavir; amsacrine; argatroban; asulacrine;azosemide; BAY-38-4766 of Bayer(N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]amino]phenyl]-3-hyrdroxy-2,2-dimethylpropanamide);bendroflumethiazide; BMS-193884 of Bristol Myers Squibb(N-(3,4-dimethyl-5-isoxazolyl)-4¹-(2-oxazolyl)-[1,1¹-biphenyl]-2-sulfonamide);bosentan; bumetide; celecoxib; chlorthalidone; delavirdine; deracoxibdofetilide; domitroban; dorzolamide; dronedarone; E-7070 of Eisai(N-(3-chloro-1H-indol-7-yl)-1,4-benzene-disulfonamide); EF-7412 ofSchwartz Pharma(N-3-[4-[4-(tetrahydro-1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)butyl]-1-piperazinyl]phenyl]ethanesulfonamide);fenquizone; furosemide; glibenclamide; gliclazide; glimepiride;glipentide; glipizide; gliquidone; glisolamide; GW-8510 of GlaxoSmithKline(4-[[6,7-dihydro-7-oxo-8H-pyrrolo[2,3-g]benzothiazol-8-ylidene)methyl]amino]-N-2-pyridinylbenzenesulfonamide);GYKI-16638 of Ivax(N-[4-[2-[[2-(2,6-dimethoxylphenoxy)-1-methlethyl]methylamino]ethyl]phenyl]methanesulfonamide);HMR-1098 of Aventis(5-chloro-2-methoxy-N-[2-[4-methoxy-3[[[(methylamino)thioxomethyl]amino]sulfonyl]phenyl]ethyl]benzamide);hydrochlorothiazide; ibutilide; indapamide; IS-741 of Ishihara(N-[2-[(ethylsufonyl)amino]-5-(trifluoromethyl)-3-pyridinyl]cyclohexanecarboxamide);JTE-522 of Japan Tobacco(4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide);KCB-328 of Chugai(N-[3-amino-4-[2-[[2-3,4-dimethoxyphenyl)ethyl]methylamino]ethoxy]phenyl]methanesulfonamide);KT2-962 of Kotobuki(3-[4-[[(4-chlorophenyl)sulfonyl]amino]butyl]-6-(1-methylethyl)-1-azulenesulfonic acid); levosulpiride; LY-295501(N-[[(3,4-dichlorophyenyl)amino]carbonyl]-2,3-dihydro-5-benzofuransulfonamide)and LY-404187 (N-2-(4-(4-cyanophenyl)phenyl)propyl-2-propanesulfonamide)of Eli Lilly; metolazone; naratriptan; nimesulide; NS-49 of Nippon((R)-N-[3-(2-amino-1-hydroxyethyl)-4-flourophenyl]methanesulfonamide);ONO-8711 of Ono((5Z)-6-[(2R,3S)-3-[[[(4-chloro-2-methylphenyl)sulfonyl]amino]methyl]bicyclo[2.2.2]oct-2-yl]-5-hexenoicacid); piretanide; PNU-103657 of Pharmacia(1-[5-methanesulfonamidoindol-2-ylcarbonyl]-4-(N-methyl-N-(3-(2-methylpropyl)-2-pyridinyl)amino)piperidine);polythiazide; ramatroban; RO-61-1790 of Hoffmann LaRoche(N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazol-5-yl)-4-pyridinyl]-4-pyrimidinyl]-5-methyl-2-pyridinesulfonamide);RPR-130737(4-hydroxy-3-[2-oxo-3(S)-[5-(3-pyridyl)thiophen-2-ylsulfonamido]pyrrolidin-1-ylmethyl]benzamide)and RPR-208707 of Aventis; S-18886(3-[(6-(4-chlorophenylsulfonylamino)-2-methyl-5,6,7,8-tetrahydronaphth]-1-yl)propionicacid) and S-32080(3-[6-(4-chlorophenylsulfonylamido)-2-propyl-3-(3pyridyl-methyl)-5,6,7,8-tetrahydronaphthalen-1-yl]propionicacid) of Server; S-36496 of Kaken(2-sulfonyl-[N-(4-chlorophenyl)sulfonylamino-butyl-N-[(4-cyclobutylthiazol-2-yl)ethenylphenyl-3-yl-methyl]]aminobenzoicacid); sampatrilat; SB-203208 of Glaxo Smith Kline (L-phenylalanine,b-methyl-,(4aR,6S,7R,7aS)-4-(aminocarbonyl)-7-[[[[[(2S,3S)-2-amino-3-methyl-1-oxopentyl]amino]sulfonyl]acetyl]amino]-7-carboxy-2,4a,5,6,7,7a-hexahydro-2-methyl-1H-cyclopenta[c]pyridine-6ylester, (bS)-); SE-170 of DuPont(2-(5-amidino-1H-indol-3-yl)N-[2′-(aminosulfonyl)-3-bromo(1,1′biphenyl)-4-yl]acetamide);sivelestat; SJA-6017 of Senju(N-(4-flourophenylsulfonyl)-L-valyl-L-leucinal); SM-19712 of Sumitomo(4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl]benzenesulfonamide);sonepiprazole; sotalol; sulfadiazine; sulfaguanole; sulfasalazine;sulpride; sulprostone; sumatriptan; T-614 of Toyama(N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonamide);T-138067(2,3,4,5,6-pentafluoro-N-(3-flouro-4-methoxyphenyl)benzenesulfonamide)and T-900607(2,3,4,5,6-pentafluoro-N-3-ureido-4-methoxyphenyl)benzenesulfonamide) ofTularik; TAK-661 of Takeda(2,2-dimethyl-3-[[7-(1-methylethyl)[1,2,4]triazolo[1,5-b]pyridazin-6-yl]oxy]-1-propanesulfonamide);tamsulosin; tezosentan; tipranavir; tirofiban; torasemide;trichloromethiazide; tripamide; valdecoxib; veralipride; xipamide; Z-335of Zeria (2-[2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]aceticacid); zafirlukast; zonisamide; and salts thereof.

In a preferred embodiment, the aminosulfonyl-comprising drug is aselective COX-2 inhibitory drug of low water solubility. Suitableselective COX-2 inhibitory drugs are compounds having the formula (III):

wherein:

A is a substituent selected from partially unsaturated or unsaturatedheterocyclic and partially unsaturated or unsaturated carbocyclic rings,preferably a heterocyclic group selected from pyrazolyl, furanoyl,isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups;

-   X is O, S or CH₂;-   n is 0 or 1;-   R¹ is at least one subsituent selected from heterocyclyl,    cycloalkyl, cycloalkenyl and aryl, and is optionally substituted at    a substitutable position with one or more radicals selected from    alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,    hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,    alkoxyalkyl, alkylsufinyl, halo, alkoxy and alkylthio;-   R² is NH₂ group;-   R³ is one or more radicals selected from hydrido, halo, alkyl,    alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy,    alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl,    heterocyclyl, cycloalkenyl, aralkyl, heterocyclyalkyl, acyl,    alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl,    aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl,    aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl,    alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,    alkylaminocarbonyl, N-arylaminocarbonyl,    N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,    alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,    N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,    N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,    N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,    alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,    N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl,    R³ being optionally substituted at a substitutable position with one    or more radicals selected from alkyl, haloalkyl, cyano, carboxyl,    alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,    alkylamino, arylamino, nitro, alkoxyalkyl, alkylsufinyl, halo,    alkoxy and alkylthio; and R⁴ is selected from hydrido and halo.

Particularly suitable selective COX-2 inhibitory drugs are compoundshaving the formula (IV):

where R⁴ is hydrogen or a C₁₋₄ alkyl or alkoxy group, X is N or CR⁵where R⁵ is hydrogen or halogen, and Y and Z are independently carbon ornitrogen atoms defining adjacent atoms of a five-to-six-membered ringthat is unsubstituted or substituted at one or more positions with oxo,halo, methyl, or halomethyl groups. Preferred such five-to six-memberedrings are cyclopentenone, furanone, methylpyrazole, isoxazole andpyridine rings substituted at no more than one position.

Illustratively, compositions of the invention are suitable forcelecoxib, deracoxib, valdecoxib and JTE-522, more particularlycelecoxib, paracoxib and valdecoxib. Other examples of suitablecompositions include Acetazolamide CAS Registry Number: 59-66-5,Acetohexamide CAS Registry Number: 968-81-0, Alpiropride CAS RegistryNumber: 81982-32-3, Althiazide CAS Registry Number: 5588-16-9, AmbusideCAS Registry Number: 3754-19-6, Amidephrine CAS Registry Number:3354-67-4, Amosulalol CAS Registry Number: 85320-68-9, Amsacrine CASRegistry Number: 51264-14-3, Argatroban CAS Registry Number: 74863-84-6,Azosemide CAS Registry Number: 27589-33-9, Bendroflumethiazide CASRegistry Number: 73-48-3, Benzthiazide CAS Registry Number: 91-33-8,Benzylhydrochlorothiazide CAS Registry Number: 1824-50-6,p-(Benzylsulfonamido)benzoic Acid CAS Registry Number: 536-95-8,Bosentan CAS Registry Number: 147536-97-8, Brinzolamide CAS RegistryNumber: 138890-62-7 Bumetanide CAS Registry Number: 28395-03-1,Butazolamide CAS Registry Number: 16790-49-1, Buthiazide CAS RegistryNumber: 2043-38-1, Carbutamide CAS Registry Number: 339-43-5, CelecoxibCAS Registry Number: 169590-42-5, Chloraminophenamide CAS RegistryNumber: 121-30-2, Chlorothiazide CAS Registry Number: 58-94-6,Chlorpropamide CAS Registry Number: 94-20-2, Chlorthalidone CAS RegistryNumber: 77-36-1, Clofenamide CAS Registry Number: 671-95-4, ClopamideCAS Registry Number: 636-54-4, Clorexolone CAS Registry Number:2127-01-7, Cyclopenthiazide CAS Registry Number: 742-20-1, CyclothiazideCAS Registry Number: 2259-96-3, Daltroban CAS Registry Number:79094-20-5, Delavirdine CAS Registry Number: 136817-59-9, Diazoxide CASRegistry Number: 364-98-7, Dichlorphenamide CAS Registry Number:120-97-8, Disulfamide CAS Registry Number: 671-88-5, Dofetilide CASRegistry Number: 115256-11-6, Domitroban CAS Registry Number:112966-96-8, Dorzolamide CAS Registry Number: 120279-96-1, Ethiazide CASRegistry Number: 1824-58-4, Ethoxzolamide CAS Registry Number: 452-35-7,Fenquizone CAS Registry Number: 20287-37-0, Flumethiazide CAS RegistryNumber: 148-56-1, N²-Formylsulfisomidine CAS Registry Number: 795-13-1,Furosemide CAS Registry Number: 54-31-9, Glibornuride CAS RegistryNumber: 26944-48-9, Gliclazide CAS Registry Number: 21187-98-4,Glimepiride CAS Registry Number: 93479-97-1, Glipizide CAS RegistryNumber: 29094-61-9, Gliquidone CAS Registry Number: 33342-05-1,Glisoxepid CAS Registry Number: 25046-79-1,N⁴-Beta-D-Glucosylsulfanilamide CAS Registry Number: 53274-53-6,Glyburide CAS Registry Number: 10238-21-8, Glybuthiazol(e) CAS RegistryNumber: 535-65-9, Glybuzole CAS Registry Number: 1492-02-0, GlyhexamideCAS Registry Number: 451-71-8, Glymidine CAS Registry Number: 339-44-6,Glypinamide CAS Registry Number: 1228-19-9, Hydrochlorothiazide CASRegistry Number: 58-93-5, Hydroflumethiazide CAS Registry Number:135-09-1, Ibutilide CAS Registry Number: 122647-31-8, Indapamide CASRegistry Number: 26807-65-8, Mafenide CAS Registry Number: 138-39-6,Mefruside CAS Registry Number: 7195-27-9, Methazolamide CAS RegistryNumber: 554-57-4, Methyclothiazide CAS Registry Number: 135-07-9,Metolazone CAS Registry Number: 17560-51-9, Naratriptan CAS RegistryNumber: 121679-13-8, Nimesulide CAS Registry Number: 51803-78-2,Noprylsulfamide CAS Registry Number: 576-97-6, Paraflutizide CASRegistry Number: 1580-83-2, Phenbutamide CAS Registry Number: 3149-00-6,Phenosulfazole CAS Registry Number: 515-54-8, Phthalylsulfacetamide CASRegistry Number: 131-69-1, Phthalylsulfathiazole CAS Registry Number:85-73-4, Sulfacetamide CAS Registry Number: 144-80-9,Sulfachlorpyridazine CAS Registry Number: 80-32-0, Sulfachrysoidine CASRegistry Number: 485-41-6, Sulfacytine CAS Registry Number: 17784-12-2,Sulfadiazine CAS Registry Number: 68-35-9, Sulfadicramide CAS RegistryNumber: 115-68-4, Sulfadimethoxine CAS Registry Number: 122-11-2,Sulfadoxine CAS Registry Number: 2447-57-6, Piretanide CAS RegistryNumber: 55837-27-9, Polythiazide CAS Registry Number: 346-18-9,Quinethazone CAS Registry Number: 73-49-4 Ramatroban CAS RegistryNumber: 116649-85-5, Salazosulfadimidine CAS Registry Number: 2315-08-4,Sampatrilat CAS Registry Number: 129981-36-8, Sematilide CAS RegistryNumber: 101526-83-4, Sivelestat CAS Registry Number: 127373-66-4,Sotalol CAS Registry Number: 3930-20-9, Soterenol CAS Registry Number:13642-52-9, Succinylsulfathiazole CAS Registry Number: 116-43-8,Suclofenide CAS Registry Number: 30279-49-3, Sulfabenzamide CAS RegistryNumber: 127-71-9, Sulfaethidole CAS Registry Number: 94-19-9,Sulfaguanole CAS Registry Number: 27031-08-9, Sulfalene CAS RegistryNumber: 152-47-6, Sulfaloxic Acid CAS Registry Number: 14376-16-0,Sulfamerazine CAS Registry Number: 127-79-7, Sulfameter CAS RegistryNumber: 651-06-9, Sulfamethazine CAS Registry Number: 57-68-1,Sulfamethizole CAS Registry Number: 144-82-1, Sulfamethomidine CASRegistry Number: 3772-76-7, Sulfamethoxazole CAS Registry Number:723-46-6, Sulfamethoxypyridazine CAS Registry Number: 80-35-3,Sulfametrole CAS Registry Number: 32909-92-5, Sulfamidochrysoidine CASRegistry Number: 103-12-8, Sulfamoxole CAS Registry Number: 729-99-7,Sulfanilamide CAS Registry Number: 63-74-1, 4-SulfanilamidosalicylicAcid CAS Registry Number: 6202-21-7, N⁴-Sulfanilylsulfanilamide CASRegistry Number: 547-52-4, Sulfanilylurea CAS Registry Number: 547-44-4,N-Sulfanilyl-3,4-xylamide CAS Registry Number: 120-34-3, Sulfaperine CASRegistry Number: 599-88-2, Sulfaphenazole CAS Registry Number: 526-08-9,Sulfaproxyline CAS Registry Number: 116-42-7, Sulfapyrazine CAS RegistryNumber: 116-44-9, Sulfapyridine CAS Registry Number: 144-83-2,Sulfarside CAS Registry Number: 1134-98-1, Sulfasalazine, CAS RegistryNumber: 599-79-1, Sulfasomizole CAS Registry Number: 632-00-8,Sulfasymazine CAS Registry Number: 1984-94-7, Sulfathiazole CAS RegistryNumber: 72-14-0, Sulfathiourea CAS Registry Number: 515-49-1,Sulfisomidine CAS Registry Number: 515-64-0, Sulfisoxazole CAS RegistryNumber: 127-69-5, Sulpiride CAS Registry Number: 15676-16-1, SulprostoneCAS Registry Number: 60325-46-4, Sulthiame CAS Registry Number: 61-56-3,Sumatriptan CAS Registry Number: 103628-46-2, Tamsulosin CAS RegistryNumber: 106133-20-4, Taurolidine CAS Registry Number: 19388-87-5,Teclothiazide CAS Registry Number: 4267-05-4, Tevenel® CAS RegistryNumber: 4302-95-8, Tirofiban CAS Registry Number: 144494-65-5,Tolazamide CAS Registry Number: 1156-19-0, Tolbutamide CAS RegistryNumber: 64-77-7, Tolcyclamide CAS Registry Number: 664-95-9, TorsemideCAS Registry Number: 56211-40-6, Trichlormethiazide CAS Registry Number:133-67-5, Tripamide CAS Registry Number: 73803-48-2, Veralipride CASRegistry Number: 66644-81-3, Xipamide CAS Registry Number: 14293-44-8,Zafirlukast CAS Registry Number: 107753-78-6, Zonisamide CAS RegistryNumber: 68291-97-4.

In a particularly preferred embodiment, the pharmaceutical compositionsof the present invention comprise a salt of celecoxib, (e.g., sodium,lithium, potassium, magnesium, or calcium salt). The salt may besignificantly more soluble in water than presently-marketed neutralcelecoxib. Due to the high pK_(a) of celecoxib (approximately 11), saltsonly form under strongly basic conditions. Typically, more than aboutone equivalent of a base is required to convert celecoxib to its saltform. A suitable aqueous solution for converting celecoxib to a salt hasa pH of about 11.0 or greater, about 11.5 or greater, about 12 orgreater, or about 13 or greater. Typically, the pH of such a solution isabout 12 to about 13. Although celecoxib is a preferred embodiment, theinvention includes other pharmaceutical drugs with a pK_(a) greater than9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, or 13. The drug may normally be ina neutral form or a salt form may already exist.

Salts of the pharmaceutical, such as celecoxib, are formed by reactionof the pharmaceutical with an acceptable base. Acceptable bases include,but are not limited to, metal hydroxides and alkoxides. Metals includealkali metals (sodium, potassium, lithium, cesium), alkaline earthmetals (magnesium, calcium), zinc, aluminum, and bismuth. Alkoxidesinclude methoxide, ethoxide, n-propoxide, isopropoxide and t-butoxide.Additional bases include arginine, procaine, and other molecules havingamino or guanidinium moieties with sufficiently high pK_(a)'s (e.g.,pK_(a)'s greater than about 11, pK_(a)'s greater than about 11.5, orpK_(a)'s greater than about 12), along with compounds having acarbon-alkali metal bond (e.g., t-butyl lithium). Sodium hydroxide andsodium ethoxide are preferred bases. The amount of base used to form asalt is typically about one or more, about two or more, about three ormore, about four or more, about five or more, or about ten or moreequivalents relative to the pharmaceutical. Preferably, about three toabout five equivalents of one or more bases are reacted with thepharmaceutical to form a salt.

A pharmaceutical salt can be transformed into a second pharmaceuticalsalt by transmetallation or another process that replaces the cation ofthe first pharmaceutical salt. In one example, a sodium salt of thepharmaceutical is prepared and is subsequently reacted with a secondsalt such as an alkaline earth metal halide (e.g., MgBr₂, MgCl₂, CaCl₂,CaBr₂), an alkaline earth metal sulfate or nitrate (e.g., Mg(NO₃)₂,Mg(SO₄)₂, Ca(NO₃)₂, Ca(SO₄)₂), or an alkaline metal salt of an organicacid (e.g. calcium formate, magnesium formate, calcium acetate,magnesium acetate, calcium propionate, magnesium propionate) to form analkaline earth metal salt of the pharmaceutical.

In a preferred embodiment of the present invention, the pharmaceuticalsalts are substantially pure. A salt that is substantially pure can begreater than about 80% pure, greater than about 85% pure, greater thanabout 90% pure, greater than about 95% pure, greater than about 98%pure, or greater than about 99% pure. Purity of a salt can be measuredwith respect to the amount of salt (as opposed to unreacted neutralpharmaceutical or base) or can be measured with respect to a specificpolymorph, co-crystal, solvate, desolvate, hydrate, dehydrate, oranhydrous form of a salt.

A pharmaceutical salt as described herein may be significantly moresoluble in water than the existing neutral form, such as the free acidalone or the presently-marketed neutral celecoxib (CELEBREX), and istypically at least about twice, at least about three times, at leastabout five times, at least about ten times, at least about twenty times,at least about fifty times, or at least about one hundred times moresoluble in water or SGF than the neutral form. CELEBREX is marketed byPfizer Inc. and G. D. Searle & Co. (Pharmacia Corporation), anddescribed on pages 2676-2680 and 2780-2784 of the 2002 edition of thePhysicians Desk Reference (also referred to herein as presently-marketedcelecoxib). The reference compounds to the present invention herein canrefer to the free acid neutral celecoxib, either crystalline oramorphous, or CELEBREX. The solubility depends on whether the salt istested alone, or as a formulation further comprising the precipitationretardants and enhancers of the invention.

After dissolution, typically in an aqueous or partially-aqueous solution(e.g., where one or more polar organic solvents are a co-solvent), thesalt can be neutralized by an acid or by dissolved gases such as carbondioxide. Typically, the pH of such a solution is 11 or less, 10 or less,or 9 or less. Neutralizing the salt results in precipitation of anamorphous or metastable crystalline form of neutral celecoxib.Typically, neutralizing a pharmaceutical salt includes protonating themajority of negatively charged anions. For celecoxib, protonationresults in the formation of amorphous and/or metastable crystallinecelecoxib, which are “neutral” (i.e., predominantly uncharged).Preferably, the neutral pharmaceutical (including amorphous and/ormetastable crystalline forms thereof, such as celecoxib) comprises 10%mol or less of charged molecules. For example, at about pH 2 (e.g.,about the pH of the stomach interior), solutions of the sodium salt ofcelecoxib precipitate immediately as an amorphous form of neutralcelecoxib. The amorphous form converts to a neutral metastablecrystalline form, which subsequently becomes the stable, needle-like,insoluble form of neutral celecoxib. For example, amorphous neutralcelecoxib formed from the salts of the present invention, e.g., thesodium salt of Example 1, converts to metastable crystalline neutralcelecoxib over about 5 to about 10 minutes. Amorphous neutral celecoxibcan be characterized by a lack of regular crystal structure, whilemetastable crystalline neutral celecoxib can be distinguished fromtypical crystalline neutral celecoxib by the PXRD pattern of isolatedmaterial.

Amorphous and metastable crystalline forms of neutral celecoxib are moresoluble and likely more readily absorbed by a subject than stablecrystalline forms of neutral celecoxib, because the energy required fora drug molecule to escape from a stable crystal is greater than theenergy required for the same drug molecule to escape from anon-crystalline, amorphous form or a metastable crystalline form.However, the instability of neutral amorphous and neutral metastablecrystalline forms makes them difficult to formulate as pharmaceuticalcompositions. As is described in U.S. Publication No. 2002/0006951, theteachings of which are incorporated herein by reference in theirentirety, without stabilization by a crystallization inhibitor, such asa polymer, amorphous neutral celecoxib converts back to a stable,insoluble crystalline form of free neutral celecoxib. These teachingsare incomplete and fall far short of the present invention however, aswe have surprisingly found that far superior formulations can be madefrom the combination of a salt or co-crystal, precipitation retardant,and an optional enhancer. Whereas others have focused on the initialsolubilization of celecoxib, the present invention is equally concernedwith dissolution and precipitation of the drug (See e.g., WO 02/102376and WO 01/78724). Moreover, until now, no one has disclosed a salt ofcelecoxib and the vital role it plays in dissolution and precipitation.Further, no one has taught the addition of an enhancer to aprecipitation retardant.

Further aspects of the invention relate to liquid formulations ofcompounds of the present invention (e.g. celecoxib). In these aspects,the drug is solubilized either directly with the precipitation retardantor with a solubilizer or solvent. Preferred solubilizers arepolyethylene oxides. More preferably, the polyethylene oxide is asurfactant. Preferred ethylene oxides comprise the functional group—(C₂H₄O)_(n)— where n≧2. Other preferred polyethylene oxides arepoloxamers having the general formulaHO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H where a≧2, where a≧3, where a≧2 andb≧30, where a≧2 and b≧4, where a≧2 and b≧50, where a≧2 and b≧60.

An aminosulfonyl containing API (celecoxib) was crystallized withmolecules comprising at least two oxygen atoms (e.g., ether groups) toexamine the physical interactions involved in precipitation retardationby the precipitation retardant. From these results, in one aspect of thepresent invention the precipitation retardant compounds, preferablysurfactants, have the following physical properties or characteristics:The retardant molecule comprises at least one, preferably two, 10, 25,40, 50, 60, 80, 100 or more functional interacting groups, wherein afunctional interacting group comprises two oxygen atoms, with each ofthe two oxygen atoms interacting (e.g., hydrogen bonding) with the API.Preferably the two oxygen atoms interact with the aminosulfonyl group ofthe API. Preferably the aminosulfonyl group is —SO₂NH₂. The twointeracting oxygen atoms are preferably separated by between about 3.6angstroms to about 5.8 angstroms, about 3.9 angstroms to about 5.5angstroms, 4.3 to about 5.2 angstroms, 4.6 to about 5.0 angstroms, orabout 4.7 to about 4.9 angstroms. In one embodiment, the two oxygenatoms are separated by at least three atoms. In another embodiment, thetwo oxygen atoms are separated by 5 atoms. In one embodiment of a 5 atomseparation, the two oxygen atoms are separated by 4 carbons and oneoxygen atom. In a more specific 5 atom separation embodiment, the orderof the 5 atoms is —C—C—O—C—C—, whereby a single unit of the functionalinteracting group (including the two interacting oxygen atoms), is—O—C—C—O—C—C—O—.

Glycol ethers can also be used as solubilizers of neutral or other formsof celecoxib including those that conform with the formula:R¹—O—((CH₂)_(m)O)_(n)—R²   (V)Wherein R¹ and R² are independently hydrogen or C₁₋₆ alkyl, C₁₋₆alkenyl, phenyl or benzyl groups, but no more than one of R¹ and R² ishydrogen; m is an integer of 2 to about 5; and n is an integer of 1 toabout 20. It is preferred that one of R¹ and R² is a C₁₋₄ alkyl groupand the other is hydrogen or a C₁₋₄ alkyl group; more preferably atleast one of R¹ and R² is a methyl or ethyl group. It is preferred thatm is 2. It is preferred that n is an integer of 1 to about 4, morepreferably 2. Non-surfactant glycol ethers, or more specifically glycolethers of formula (V) and above, can also be specifically excluded fromthe present invention. Preferably, the glycol ethers are surfactants.

Compositions of the present invention optionally comprise one or morepharmaceutically acceptable co-solvents. Non-limiting examples ofco-solvents suitable for use in compositions of the present inventioninclude any glycol ether listed above; alcohols, for example ethanol andn-butanol; glycols not listed above; for example propylene glycol,1,3-butanediol and polyethylene glycol such as PEG-400; oleic andlinoleic acid triglycerides, for example soybean oil; caprylic/caprictriglycerides, for example Miglyol™ 812 of Huls; caprylic/capric mono-and diglycerides, for example Capmul™ MCM of Abitec; polyoxyethylenecaprylic/capric glycerides such as polyoxyethylene caprylic/capric mono-and diglycerides, for example Labrasol™ of Gattefosse; propylene glycolfatty acid esters, for example propylene glycol laurate; polyoxyethylenecastor oil, for example Cremophor™ EL of BASF; polyoxyethylene glyceryltrioleate, for example Tagat™ TO of Goldschmidt; and lower alkyl estersof fatty acids, for example ethyl butyrate, ethyl caprylate and ethyloleate.

Celecoxib salts are preferred because they are stable, such that theycan be formulated as pharmaceutical compositions and stored beforeadministration to a subject. Only after dissolution and subsequentneutralization do the celecoxib salts precipitate as or transform intosubstantially amorphous neutral and then substantially metastablecrystalline neutral forms. Preferably, dissolution and neutralization ofcelecoxib salts occur in situ in the gastrointestinal tract of a subject(e.g., stomach, duodenum, ileum), such that a maximal amount ofamorphous and/or metastable crystalline neutral celecoxib is presentwith a maximum amount of celecoxib in solution after administration(e.g., in vivo), rather than before administration.

The salts, hydrates, and solvates of the present invention arenon-limiting examples of species which can be solubilized moreeffectively in water, SGF, and/or SIF than their respective free forms.For example, celecoxib sodium is more soluble in water than celecoxibfree acid. A “spring” is defined as a high energy species that drivessupersaturation of the API. Such a high energy species is less stableand, therefore, more soluble than an analogous relatively more stableform (e.g., free form, polymorph, etc.). The intrinsic solubility of ahigh energy species can be 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 25, 50, 75,100 or more times greater than for an analogous more stable form. Aspring can be in the form of, for example, a free acid, a free base, asalt, a liquid, a hydrate, a solvate, a co-crystal, etc. In thisexample, the sodium salt acts as a “spring” to drive the supersaturationof the API. One embodiment of the present invention provides for an APIin a form with improved aqueous solubility. Once dissolution takesplace, inhibition of precipitation becomes important. The inhibition ofprecipitation acts as a “parachute” to slow the rate of APIprecipitating from solution. Another embodiment of the present inventionprovides for an API in a formulation which inhibits precipitation uponinitial dissolution. Both aspects are of great importance in apharmaceutical composition. The ability of a pharmaceutical compositionto solubilize an API and to maintain the API in solution for a durationlong enough to cause the desired therapeutic effect is vital.

Dissolution Modulation:

In another aspect of the present invention, the dissolution profile ofthe API is modulated whereby the aqueous dissolution rate or thedissolution rate in simulated gastric fluid or in simulated intestinalfluid, or in a solvent or plurality of solvents is increased.Dissolution rate is the rate at which API solids dissolve in adissolution medium. For APIs whose absorption rates are faster than thedissolution rates (e.g., steroids), the rate-limiting step in theabsorption process is dissolution. Because of a limited residence timeat the absorption site, APIs that are not dissolved before they areremoved from the intestinal absorption site are considered useless.Therefore, the rate of dissolution has a major impact on the performanceof APIs that are poorly soluble. Because of this factor, the dissolutionrate of APIs in solid dosage forms is an important, routine, qualitycontrol parameter used in the API manufacturing process.Dissolution rate=K S (C _(s)-C)where K is the dissolution rate constant, S is the surface area, C_(s)is the apparent solubility (saturated concentration), and C is theconcentration of API in the dissolution media. For rapid API absorption,C_(s)-C is approximately equal to C_(s). The dissolution rate of APIsmay be measured by conventional means known in the art.

The increase in the dissolution rate of a composition of the presentinvention, as compared to the neutral free form, may be specified, suchas by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 2, 3, 4, 5, 6,7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250,300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than the freeform in the same solution. Conditions under which the dissolution rateis measured are discussed above. The increase in dissolution may befurther specified by the time the composition remains supersaturated.

Examples of above embodiments include: compositions with a dissolutionrate, at 37 degrees C. and a pH of 7.0, that is increased at least 5fold over the neutral free form, compositions with a dissolution rate inSGF that is increased at least 5 fold over the neutral free form,compositions with a dissolution rate in SIF that is increased at least 5fold over the neutral free form.

The present invention demonstrates that the length of time in whichcelecoxib or other APIs remain in solution can be increased to asurprising high degree by using a salt or co-crystal form with thepresence of a precipitation retardant, normally a surfactant (e.g.,poloxamer, TPGS, SDS, etc.) and an optional enhancer (e.g.,hydroxypropyl cellulose) as discussed herein. The presence of theseagents allows the formation of a supersaturated solution of the API anda relatively high concentration of API will remain in solution for anextended period of time (as compared to the neutral free acid). Thepresence of these components does not preclude the presence of otherfurther agents, including further surfactants such as, polyethyleneglycol and polyoxyethylene sorbitan esters. The additional presence ofother suitable surfactants is also not precluded and these are listedherein. Further additional agents which might slow the rate ofprecipitation such as polyvinylpyrrolidone are also not precluded.Neutral free celecoxib, for example, has a solubility in water of lessthan 1 microgram/mL and cannot be maintained as a supersaturatedsolution for any appreciable time. The present invention has drawncompositions that can be maintained for a period of time (e.g., 15, 30,45, 60 minutes and longer) as supersaturated solutions at concentrations2, 3, 5, 7, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater, orsolubilities increased by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40,50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000,or 100,000 fold over the neutral free form in the same solution (e.g.,water or SGF).

The amount of precipitation inhibitor or enhancer may each or togetherbe less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 70, 80, or 90 percent w/w of the formulated pharmaceutical.The percent w/w for either or both precipitation inhibitor and enhancermay also be in a range represented by any two integers of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, or 90.

Celecoxib salts of the present invention are typically stable (i.e.,more than 90% of the celecoxib salt does not change in composition orcrystalline structure) for at least about one week, at least about onemonth, at least about two months, at least about three months, at leastabout six months, at least about nine months, at least about one year,or at least about two years at room temperature in the absence ofmoisture. Room temperature typically ranges from about 15 degrees C. toabout 30 degrees C. The absence of moisture, as defined herein, refersto celecoxib salts not contacting quantities of liquid, particularlywater or alcohols. For purposes of the present invention, gases such aswater vapor are not considered to be moisture.

The compositions of the present invention, including the activepharmaceutical ingredient (API) and formulations comprising the API, aresuitably stable for pharmaceutical use. Preferably, the API orformulations thereof of the present invention are stable such that whenstored at 30 degrees C. for 2 years, less than 0.2% of any one degradantis formed. The term degradant refers herein to product(s) of a singletype of chemical reaction. For example, if a hydrolysis event occursthat cleaves a molecule into two products, for the purpose of thepresent invention, it would be considered a single degradant. Morepreferably, when stored at 40 degrees C. for 2 years, less than 0.2% ofany one degradant is formed. Alternatively, when stored at 30 degrees C.for 3 months, less than 0.2% or 0.15%, or 0.1% of any one degradant isformed, or when stored at 40 degrees C. for 3 months, less than 0.2% or0.15%, or 0.1% of any one degradant is formed. Further alternatively,when stored at 60 degrees C. for 4 weeks, less than 0.2% or 0.15%, or0.1% of any one degradant is formed. The relative humidity (RH) may bespecified as ambient (RH), 75% (RH), or as any single integer between 1to 99% (RH).

Bioavailability Modulation:

The methods of the present invention are used to make a pharmaceuticalAPI formulation with greater solubility, dissolution, bioavailability,AUC, reduced time to T_(max), the average time from administration toreach peak blood serum levels, higher C_(max), the average maximum bloodserum concentration of API following administration, and longer T_(1/2),the average terminal half-life of API blood serum concentrationfollowing T_(max), when compared to the neutral free form.

AUC is the area under the curve of plasma concentration of API (notlogarithm of the concentration) against time after API administration.The area is conveniently determined by the “trapezoidal rule”: The datapoints are connected by straight line segments, perpendiculars areerected from the abscissa to each data point, and the sum of the areasof the triangles and trapezoids so constructed is computed. When thelast measured concentration (C_(n), at time t_(n)) is not zero, the AUCfrom t_(n) to infinite time is estimated by C_(n)/k_(el).

The AUC is of particular use in estimating bioavailability of APIs, andin estimating total clearance of APIs (Cl_(T)). Following singleintravenous doses, AUC=D/Cl_(T), for single compartment systems obeyingfirst-order elimination kinetics Alternatively, AUC=C₀/k_(el). Withroutes other than the intravenous, AUC=F·D/Cl_(T), where F is theabsolute bioavailability of the API.

Thus, in a further aspect, the present invention provides a process formodulating the bioavailability of an API when administered in its normaland effective dose range, whereby the AUC is increased, the time toT_(max) is reduced, or C_(max) is increased, which process comprises:

(1) forming a salt or co-crystal of an API;

(2) combining the salt or co-crystal with a precipitation retardant, andoptionally, further with an enhancer.

Examples of the above embodiments include: compositions with a time toT_(max) that is reduced by at least 10% as compared to the neutral freeform, compositions with a time to T_(max) that is reduced by at least20% over the free form, compositions with a time to T_(max) that isreduced by at least 40% over the free form, compositions with a time toT_(max) that is reduced by at least 50% over the free form, compositionswith a T_(max) that is reduced by at least 60% over the free form,compositions with a T_(max) that is reduced by at least 70% over thefree form, compositions with a T_(max) that is reduced by at least 80%over the free form, compositions with a C_(max) that is increased by atleast 20% over the free form, compositions with a C_(max) that isincreased by at least 30% over the free form, compositions with aC_(max) that is increased by at least 40% over the free form,compositions with a C_(max) that is increased by at least 50% over thefree form, compositions with a C_(max) that is increased by at least 60%over the free form, compositions with a C_(max) that is increased by atleast 70% over the free form, compositions with a C_(max) that isincreased by at least 80% over the free form, compositions with an AUCthat is increased by at least 10% over the free form, compositions withan AUC that is increased by at least 20% over the free form,compositions with an AUC that is increased by at least 30% over the freeform, compositions with an AUC that is increased by at least 40% overthe free form, compositions with an AUC that is increased by at least50% over the free form, compositions with an AUC that is increased by atleast 60% over the free form, compositions with an AUC that is increasedby at least 70% over the free form, or compositions with an AUC that isincreased by at least 80% over the free form.

The uptake of a drug by a subject can also be assessed in terms ofmaximum blood serum concentration and time to reach maximum blood serumconcentration. Pharmaceutical compositions with a more rapid onset totherapeutic effect typically reach a higher maximum blood serumconcentration (C_(max)) a shorter time after oral administration(T_(max)). Preferably, compositions, preferably including salts, of thepresent invention have a higher C_(max) and/or a shorter T_(max) thanpresently-marketed celecoxib. The T_(max) for the compositions of thepresent invention occurs within about 60 minutes, 55 minutes, 50minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20minutes, 15 minutes, 10 minutes, or within about 5 minutes ofadministration (e.g., oral administration). Even more preferably, thetherapeutic effects of compositions of the present invention begin tooccur within about 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40minutes, 35 minutes, 30 minutes, within about 25 minutes, within about20 minutes, within about 15 minutes, within about 10 minutes, or withinabout 5 minutes of administration (e.g., oral administration). In U.S.Pat. No. 6,579,895, Karim et al. report about a 2.5-fold increase inC_(max) over that of presently-marketed celecoxib (CELEBREX) by thesuspension of neutral free form celecoxib particles in an aqueousliquid. The present invention produces an increase in C_(max) of aboutfour-fold over that of the presently-marketed drug. In addition, thepresent invention yields an increase in the AUC of at least abouttwo-fold over that of presently-marketed celecoxib.

Compositions of the present invention have a bioavailability greaterthan neutral celecoxib and currently-marketed CELEBREX. In severalembodiments, the compositions of the present invention have abioavailability of at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 87%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% greater than that ofneutral celecoxib and currently-marketed CELEBREX.

Administration of the present invention to a subject may result ineffective pain relief. The desired therapeutic effect calls for interalia an appropriate blood serum concentration of the API. Effectiveblood serum concentrations of celecoxib can range based on many factors(e.g., age, weight, etc.) but generally are about 10 ng/mL to about 500ng/mL, or about 25 ng/mL to 400 ng/mL, or about 50 ng/mL to about 300ng/mL. Specifically, about 250 ng/mL is often suitable for effectivepain relief. In general, an effective dosage of celecoxib will be foundin the range of about 1 mg/kg to about 6 mg/kg body weight. For anaverage 75 kg subject, this range equates to a celecoxib dose of about75 mg to about 450 mg. This is particularly in view of the extensivebinding of celecoxib to plasma albinum which was known to occurfollowing oral administration (Davies et al., Clin. Pharmacokinet.38:225-242, 2000 and U.S. Pat. No. 6,579,895 are herein incorporated asreferences in their entirety). Thus, one could not have predicted that aparticular blood serum concentration would produce analgesia.

An “effective pain-relieving concentration” or “effective pain-relievingblood serum concentration” as used herein is intended to mean a bloodserum level in a patient which when tested in a standardized testinvolving patient scoring of the severity of pain, achieves a mean scoreindicating pain relief. In one such test as described herein below,patients score pain on a scale of from 0 (no reduction in severity ofpain) to 4 (complete relief of pain) and a mean score equal to orgreater than a given value is deemed to constitute effectivepain-relief. A mean score of 0.5 or greater and, more preferably, 1.0 orgreater in such a test, as exemplified herein, is deemed to constituteeffective pain relief. The skilled artisan will appreciate, however,that other approaches can be used to assess the severity of pain andrelief from such pain.

Thus, one aspect of the present invention involves a therapeutic methodfor analgesia in which a composition comprising a celecoxib salt orco-crystal is administered orally to a subject, in a formulation thatprovides detectable pain relief not later than about 30 minutes afteroral administration. By “detectable pain relief”, it is meant that theformulation produces effective pain relief that is measurable by astandard method such as that described above. For example, aformulation, which achieves a mean score of 0.5 or greater and, morepreferably, 1.0 or greater on a scale of from 0 to 4 in a testing systemas described above, is deemed to provide detectable pain relief. Theinvention is not limited to use of any particular type of formulation,so long as it exhibits the pharmacokinetic profile defined herein.Examples of suitable formulation types are described below.

Protocols for conducting human pharmacokinetic studies are well known inthe art and any standard protocol can be used to determine whether aparticular celecoxib formulation satisfies the pharmacokinetic criteriaset out herein. An example of a suitable protocol is described below.

An advantage of the present invention is that relief of pain, evenintense pain as can occur, for example, following oral, general ororthopedic surgery, is achieved significantly faster, i.e., in asignificantly shorter time after administration, than is achievable withstandard formulations of celecoxib.

Any standard pharmacolinetic protocol can be used to determine bloodserum concentration profile in humans following oral administration of acelecoxib formulation, and thereby establish whether that formulationmeets the pharmacokinetic criteria set out herein.

Illustratively, a randomized single-dose crossover study can beperformed using a group of healthy adult human subjects. The number ofsubjects is sufficient to provide adequate control of variation in astatistical analysis, and is typically about 10 or greater, although forcertain purposes a smaller group can suffice. Each subject receives, byoral administration at time zero, a single dose (e.g., 200 mg) of a testformulation of celecoxib, normally at around 8 am following an overnightfast. The subject continues to fast and remains in an upright positionfor about 4 hours after administration of the celecoxib formulation.Blood samples are collected from each subject before administration(e.g., 15 minutes prior to administration) and at several intervalsafter administration. For the present purpose it is preferred to takeseveral samples within the first hour, and to sample less frequentlythereafter. Illustratively, blood samples can be collected 15, 30, 45,60 and 90 minutes after administration, then every hour from 2 to 10hours after administration. Optionally additional blood samples can betaken later, for example 12 and 24 hours after administration. If thesame subjects are to be used for study of a second test formulation, aperiod of at least 7 days is allowed to elapse before administration ofthe second formulation. Plasma is separated from the blood samples bycentrifugation and the separated plasma is analyzed for celecoxib by avalidated high performance liquid chromatography (HPLC) procedure with alower limit of detection of 10 ng/nL (see for example, Paulson et al.,Drug Metab. Dispos. 27:1133-1142, 1999; Paulson et al., Drug Metab.Dispos. 28:308-314, 2000; Davies et al). Blood serum concentrations ofcelecoxib referenced herein are intended to mean total celecoxibconcentrations including both free and bound celecoxib as determinedupon extraction from the plasma sample and HPLC detection according tomethods known in the art such as those identified above. Ailmentstreatable with celecoxib and salts thereof of the present invention arediscussed below. Treatment of chronic pain is a preferred embodiment ofthe present invention.

Dose Response Modulation:

In a further aspect the present invention provides a process forimproving the dose response of an API by making a composition of thepresent invention.

Dose response is the quantitative relationship between the magnitude ofresponse and the dose inducing the response and may be measured byconventional means known in the art. The curve relating effect(dependent variable) to dose (independent variable) for an API-cellsystem is the “dose-response curve”. Typically, the dose-response curveis the measured response to an API plotted against the dose of the API(mg/kg) given. The dose response curve can also be a curve of AUCagainst the dose of the API given.

The dose-response curve for presently-marketed celecoxib is nonlinear.Preferably, the dose-response curve for celecoxib salt and co-crystalcompositions of the present invention is linear or contains a largerlinear region than presently-marketed celecoxib. Also, the absorption oruptake of presently-marketed celecoxib depends in part on food effects,such that uptake of celecoxib increases when taken with food, especiallyfatty food. Preferably, uptake of celecoxib salts of the presentinvention exhibits a decreased dependence on food, such that thedifference in uptake of celecoxib salts when taken with food and whennot taken with food is less than the difference in uptake ofpresently-marketed celecoxib.

Decreasing Hygroscopicity:

In a still further aspect the present invention provides for APIs withdecreased hygroscopicity and a method for decreasing the hygroscopicityof an API by making the same. An aspect of the present inventionprovides a pharmaceutical composition of an API that is less hygroscopicthan amorphous or crystalline free form. Hygroscopicity can be assessedby dynamic vapor sorption analysis, in which 5-50 mg of the compound issuspended from a Cahn microbalance. The compound being analyzed shouldbe placed in a non-hygroscopic pan and its weight should be measuredrelative to an empty pan composed of identical material and havingnearly identical size, shape, and weight. Ideally, platinum pans shouldbe used. The pans should be suspended in a chamber through which a gas,such as air or nitrogen, having a controlled and known percent relativehumidity (% RH) is flowed until eqilibrium criteria are met. Typicalequilibrium criteria include weight changes of less than 0.01% changeover 3 minutes at constant humidity and temperature. The relativehumidity should be measured for samples dried under dry nitrogen toconstant weight (<0.01% change in 3 minutes) at 40 degrees C. unlessdoing so would de-solvate or otherwise convert the material to anamorphous compound. In one aspect, the hygroscopicity of a driedcompound can be assessed by increasing the RH from 5 to 95% inincrements of 5% RH and then decreasing the RH from 95 to 5% in 5%increments to generate a moisture sorption isotherm. The sample weightshould be allowed to equilibrate between each change in % RH. If thecompound deliquesces or becomes amorphous above 75% RH but below 95% RH,the experiment should be repeated with a fresh sample and the relativehumidity range for the cycling should be narrowed to 5-75% RH or 10-75%RH instead of 5-95% RH. If the sample cannot be dried prior to testingdue to lack of form stability, than the sample should be studied usingtwo complete humidity cycles of either 10-75% RH or 5-95% RH, and theresults of the second cycle should be used if there is significantweight loss at the end of the first cycle.

Hygroscopicity can be defined using various parameters. For purposes ofthe present invention, a non-hygroscopic molecule should not gain orlose more than 1.0%, or more preferably, 0.5% weight at 25 degrees C.when cycled between 10 and 75% RH (relative humidity at 25 degrees C.).The non-hygroscopic molecule more preferably should not gain or losemore than 1.0%, or more preferably, 0.5% weight when cycled between 5and 95% RH at 25 degrees C., or 0.25% of its weight between 10 and 75%RH. Most preferably, a non-hygroscopic molecule will not gain or losemore than 0.25% of its weight when cycled between 5 and 95% RH.

Alternatively, for purposes of the present invention, hygroscopicity canbe defined using the parameters of Callaghan et al., EquilibriumMoisture Content of Pharmaceutical Excipients, in API Dev. Ind. Pharm.,Vol. 8, pp. 335-369 (1982). Callaghan et al. classified the degree ofhygroscopicity into four classes. Class 1: Non-hygroscopic Essentiallyno moisture increases occur at relative humidities below 90%. Class 2:Slightly hygroscopic Essentially no moisture increases occur at relativehumidities below 80%. Class 3: Moderately hygroscopic Moisture contentdoes not increase more than 5% after storage for 1 week at relativehumidities below 60%. Class 4: Very hygroscopic Moisture contentincrease may occur at relative humidities as low as 40 to 50%.

Alternatively, for purposes of the present invention, hygroscopicity canbe defined using the parameters of the European Pharmacopoeia TechnicalGuide (1999, p. 86) which has defined hygroscopicity, based on thestatic method, after storage at 25 degrees C. for 24 h at 80% RH:

Slightly hygroscopic: Increase in mass is less than 2% m/m and equal toor greater than 0.2% m/m.

Hygroscopic: Increase in mass is less than 15% m/m and equal to orgreater than 0.2% m/m.

Very Hygroscopic: Increase in mass is equal to or greater than 15% m/m.

Deliquescent: Sufficient water is absorbed to form a liquid.

Compositions of the present invention can be set forth as being in Class1, Class 2, or Class 3, or as being Slightly hygroscopic, Hygroscopic,or Very Hygroscopic. Compositions of the present invention can also beset forth based on their ability to reduce hygroscopicity. Thus,preferred compositions of the present invention are less hygroscopicthan the neutral free form. Further included in the present inventionare compositions that do not gain or lose more than 1.0% weight at 25degrees C. when cycled between 10 and 75% RH, wherein the referencecompound gains or loses more than 1.0% weight under the same conditions.Further included in the present invention are compositions that do notgain or lose more than 0.5% weight at 25 degrees C. when cycled between10 and 75 % RH, wherein the reference compound gains or loses more than0.5% or more than 1.0% weight under the same conditions. Furtherincluded in the present invention are compositions that do not gain orlose more than 1.0% weight at 25 degrees C. when cycled between 5 and95% RH, wherein the reference compound gains or loses more than 1.0%weight under the same conditions. Further included in the presentinvention are compositions that do not gain or lose more than 0.5%weight at 25 degrees C. when cycled between 5 and 95% RH, wherein thereference compound gains or loses more than 0.5% or more than 1.0%weight under the same conditions. Further included in the presentinvention are compositions that do not gain or lose more than 0.25%weight at 25 degrees C. when cycled between 5 and 95% RH, wherein thereference compound gains or loses more than 0.5% or more than 1.0%weight under the same conditions.

Further included in the present invention are compositions that have ahygroscopicity (according to Callaghan et al.) that is at least oneclass lower than the reference compound or at least two classes lowerthan the reference compound. Included are a Class 1 composition of aClass 2 reference compound, a Class 2 composition of a Class 3 referencecompound, a Class 3 composition of a Class 4 reference compound, a Class1 composition of a Class 3 reference compound, a Class 1 composition ofa Class 4 reference compound, or a Class 2 composition of a Class 4reference compound.

Further included in the present invention are compositions that have ahygroscopicity (according to the European Pharmacopoeia Technical Guide)that is at least one class lower than the reference compound or at leasttwo classes lower than the reference compound. Non-limiting examplesinclude a Slightly hygroscopic composition of a Hygroscopic referencecompound, a Hygroscopic composition of a Very Hygroscopic referencecompound, a Very Hygroscopic composition of a Deliquescent referencecompound, a Slightly hygroscopic composition of a Very Hygroscopicreference compound, a Slightly hygroscopic composition of a Deliquescentreference compound, a Hygroscopic composition of a Deliquescentreference compound.

In another aspect of the present invention, a correlation exists betweenin vivo dissolution and in vitro dissolution. For example, dissolutionof celecoxib sodium hydrate formulations in SGF at 37 degrees C. iscomparable to the pharmacokinetic data obtained in dogs in Example 7.For instance, the magnitude of C_(max) in the pharmacokinetic studycorrelates with the C_(max) obtained with in vitro studies completedwith PLURONIC F127 and HPC at equal weight ratios to celecoxib freeacid. Other pharmacokinetic parameters such as, for example, T_(max) andAUC, can also be closely related between both types of experiments.

Celecoxib salts can be characterized by differential scanningcalorimetry (DSC). The sodium salt of celecoxib prepared in Example 1 ischaracterized by at least 3 overlapping endothermic transitions between50 degrees C. and 110 degrees C. (FIG. 1). Conditions for DSC can befound in the Exemplification.

Celecoxib salts can be characterized by thermogravimetric analysis(TGA). The sodium salt product prepared by Example 1 was characterizedby TGA, and was determined to have about 3 loosely bound equivalents ofwater that evaporated between about 30 degrees C. and about 40 degreesC., one more tightly bound equivalent of water that evaporated betweenabout 40 degrees C. and about 100 degrees C., and one very tightly boundequivalent of water that evaporated between about 140 degrees C. andabout 160 degrees C. (FIG. 2). As described herein however, the sodiumsalt can exist at different states of hydration depending on thehumidity, temperature, and other conditions. Conditions for TGA can befound in the Exemplification section.

Celecoxib salts of the present invention can also be characterized bypowder X-ray diffraction (PXRD). The sodium salt of celecoxib preparedby Example 1 had an intense reflection or peak at a 2-theta angle of6.36 degrees, and other reflections or peaks at 7.01, 16.72, and 20.93degrees (FIG. 3). Conditions for PXRD can be found in theExemplification.

In one embodiment of the present invention, a solid form of celecoxibshows a characteristic absence of a Raman scattering peak at 906 cm⁻¹(e.g., salts, solvates, etc.). The Raman scattering spectrum ofcelecoxib free acid comprises a peak at this position.

Celecoxib salts may comprise solvate molecules and can occur in avariety of solvation states, also known as solvates. Thus, celecoxibsalts can exist as crystalline polymorphs. Polymorphs are differentcrystalline forms of the same drug substance, and in the present use ofthe term include solvates and hydrates. For example, differentpolymorphs of a celecoxib salt can be obtained by varying the method ofpreparation (compare Examples). Crystalline polymorphs typically havedifferent solubilities, such that a more thermodynamically stablepolymorph is less soluble than a less thermodynamically stablepolymorph. Pharmaceutical polymorphs can also differ in properties suchas shelf-life, bioavailability, morphology, vapor pressure, density,color, and compressibility.

Suitable solvate molecules include water, alcohols, other polar organicsolvents, and combinations thereof. Alcohols include methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, propylene glycol andt-butanol. Propylene glycol solvates are particularly preferred becausethey are more stable and less hygroscopic than other forms. Alcoholsalso include polymerized alcohols such as polyalkylene glycols (e.g.,polyethylene glycol, polypropylene glycol). In an embodiment, water isthe solvent. In embodiments of the invention, a celecoxib salt containsabout 0.0%, less than 0.5%, 0.5, less than 1.0%, 1.0, less than 1.5%,1.5, less than 2.0%, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 or about 6.0equivalents, or about 1.0 to about 6.0, 2.0 to about 5.0, 3.0 to about6.0, 3.0 to about 5.0, 1.0 to about 4.0, 2.0 to about 4.0, 1.0 to about3.0, 2.0 to about 3.0, 0.0 to about 3.0, 0.5 to about 3.0, 0.0 to about2.0, 0.5 to about 2.0, 0.0 to about 1.5, 0.5 to about 1.5, 1.0 to about1.5, or 0.5 to about 1.0 equivalents of water per equivalent of salt.The amount of water equivalents in the above hydrates is primarilyaffected by the experimental conditions (e.g., temperature). Solvatemolecules can be removed from a crystalline salt, such that the salt iseither a partial or complete desolvate. If the solvate molecule is water(forming a hydrate), then a desolvated salt is said to be a dehydrate. Asalt with all water removed is anhydrous. Solvate molecules can beremoved from a salt by methods such as heating, treating under vacuum orreduced pressure, blowing dry air over a salt, or a combination thereof.Following desolvation, there are typically about one to about fiveequivalents, about one to about four equivalents, about one to aboutthree equivalents, or about one to about two equivalents of solvent perequivalent of salt in a crystal.

Pharmaceuticals including celecoxib, can co-crystallize with one or moreother substances. The term “co-crystal” as used herein means acrystalline material comprised of two or more unique solids at roomtemperature, each containing distinctive physical characteristics, suchas structure, melting point and heats of fusion. Solvates of APIcompounds that do not further comprise a co-crystal forming compound arenot co-crystals according to the present invention. The co-crystals mayhowever, include one or more solvent molecules in the crystallinelattice. That is, solvates of co-crystals, or a co-crystal furthercomprising a solvent or compound that is a liquid at room temperature,is included in the present invention, but crystalline material comprisedof only one solid and one or more liquids (at room temperature) are notincluded by the term “co-crystal”. The co-crystals may include aco-crystal former and a salt of an API, but the API and the co-crystalformer of the present invention are constructed or bonded togetherthrough hydrogen bonds. Other modes of molecular recognition may also bepresent including, II-stacking, guest-host complexation and van derWaals interactions. Of the interactions listed above, hydrogen-bondingis the dominant interaction in the formation of the co-crystal, wherebya non-covalent bond is formed between a hydrogen bond donor of one ofthe moieties and a hydrogen bond acceptor of the other. An alternativeembodiment provides for a co-crystal wherein the co-crystal former is asecond API. In another embodiment, the co-crystal former is not an API.

In several embodiments of the present invention, the composition is aco-crystal. In other embodiments the co-crystal formers are selectedfrom one or two (for ternary co-crystals) of the following: saccharin,nicotinamide, pyridoxine (4-pyridoxic acid), acesulfame, glycine,arginine, asparagine, cysteine, glutamine, histidine, isoleucine,lysine, methionine, phenylalanine, proline, threonine, tyrosine, valine,aspartic acid, glutamic acid, tryptophan, adenine, acetohydroxamic acid,alanine, allopurinaol, 4-aminobenzoic acid, cyclamic acid,4-ethoxyphenyl urea, 4-aminopyridine, leucine, nicotinic acid, serine,tris, vitamin k5, xylito, succinic acid, tartaric acid, pyridoxamine,ascorbic acid, hydroquinone, salicylic acid, benzoic acid, caffeine,benzenesulfonic acid, 4-chlorobenzene-sulfonic acid, citric acid,fumaric acid, gluconic acid, glutaric acid, glycolic acid, hippuricacid, maleic acid, malic acid, mandelic acid, malonic acid,1,5-napthalene-disulfonic acid (armstrong's acid), clemizole, imidazole,glucosamine, piperazine, procaine, or urea.

In another embodiment of the present invention, a solid form ofcelecoxib can give rise to a distinct PXRD diffractogram. This can becaused by polymorphism, a variable hydrate, a different environmentalcondition, etc. In one embodiment, the propylene glycol solvate ofcelecoxib sodium salt can yield a PXRD pattern with theabsence orpresence of a peak at 8.21 degrees 2-theta. In another embodiment, thepropylene glycol solvate of celecoxib sodium salt can yield a PXRDpattern with theabsence or presence of a peak at 8.79 degrees 2-theta.

In another embodiment, a trihydrate of the propylene glycol solvate ofcelecoxib sodium salt is observed under 10 to 60 percent relativehumidity (RH). In another embodiment, an anhydrous form of the propyleneglycol solvate of celecoxib sodium salt is observed under 0 percentrelative humidity (RH). In another embodiment, a dihydrate of thepropylene glycol solvate of celecoxib sodium salt is observed under 40to 60 percent relative humidity (RH). In another embodiment, amonohydrate of the celecoxib sodium salt is observed under 10 to 20percent relative humidity (RH). In another embodiment, a trihydrate ofthe celecoxib sodium salt is observed under 40 to 70 percent relativehumidity (RH). In another embodiment, an anhydrous form of the propyleneglycol solvate of celecoxib potassium salt is observed under 0 to 40percent relative humidity (RH).

Celecoxib salts may be prepared by contacting celecoxib with a solvent.Suitable solvents include water, alcohols, other polar organic solvents,and combinations thereof. Water and isopropanol are preferred solvents.Celecoxib is reacted with a base, where suitable bases are listed above,such that celecoxib forms a salt and preferably dissolves. Bases can beadded to celecoxib with the solvent (i.e., dissolved in the solvent),such that celecoxib is solvated and deprotonated essentiallysimultaneously, or bases can be added after the celecoxib has beencontacted with solvent (e.g., see Examples). In the latter scenario,bases can either be dissolved in a solvent, which can be either thesolvent already contacting celecoxib or a different solvent, can beadded as a neat solid or liquid, or a combination thereof. Sodiumhydroxide and sodium ethoxide are preferred bases. The amount of baserequired is discussed above. The solvent can be evaporated to obtaincrystals of the celecoxib salt, or the celecoxib salt may precipitateand/or crystallize independent of evaporation. Crystals of a celecoxibsalt can be filtered to remove bulk solvent. Methods of removingsolvated solvent molecules are discussed above.

Excipients employed in pharmaceutical compositions of the presentinvention can be solids, semi-solids, liquids or combinations thereof.Preferably, excipients are solids. Compositions of the inventioncontaining excipients can be prepared by any known technique of pharmacythat comprises admixing an excipient with a drug or therapeutic agent. Apharmaceutical composition of the invention contains a desired amount ofcelecoxib per dose unit and, if intended for oral administration, can bein the form, for example, of a tablet, a caplet, a pill, a hard or softcapsule, a lozenge, a cachet, a dispensable powder, granules, asuspension, an elixir, a dispersion, a liquid, or any other formreasonably adapted for such administration. If intended for parenteraladministration, it can be in the form, for example, of a suspension ortransdermal patch. If intended for rectal administration, it can be inthe form, for example, of a suppository. Presently preferred are oraldosage forms that are discrete dose units each containing apredetermined amount of the drug, such as tablets or capsules.

Non-limiting examples of excipients that can be used to preparepharmaceutical compositions of the invention follow.

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable carriers or diluents as excipients.Suitable carriers or diluents illustratively include, but are notlimited to, either individually or in combination, lactose, includinganhydrous lactose and lactose monohydrate; starches, including directlycompressible starch and hydrolyzed starches (e.g., Celutab™ and Emdex™);mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000) anddextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-baseddiluents; confectioner's sugar; monobasic calcium sulfate monohydrate;calcium sulfate dihydrate; granular calcium lactate trihydrate;dextrates; inositol; hydrolyzed cereal solids; amylose; cellulosesincluding microcrystalline cellulose, food grade sources of alpha- andamorphous cellulose (e.g., RexcelJ), powdered cellulose, andhydroxypropylmethylcellulose (HPMC); calcium carbonate; glycine;bentonite; block co-polymers; polyvinylpyrrolidone; and the like. Suchcarriers or diluents, if present, constitute in total about 5% to about99%, preferably about 10% to about 85%, and more preferably about 20% toabout 80%, of the total weight of the composition. The carrier,carriers, diluent, or diluents selected preferably exhibit suitable flowproperties and, where tablets are desired, compressibility.

Lactose, mannitol, dibasic sodium phosphate, and microcrystallinecellulose (e.g., Avicel™ PH (of FMC)), either individually or incombination, are preferred diluents. These diluents are chemicallycompatible with celecoxib. The use of extragranular microcrystallinecellulose (that is, microcrystalline cellulose added to a granulatedcomposition) can be used to improve hardness (for tablets) and/ordisintegration time. Lactose, especially lactose monohydrate, isparticularly preferred. Lactose typically provides compositions havingsuitable release rates of celecoxib, stability, pre-compressionflowability, and/or drying properties at a relatively low diluent cost.It provides a high density substrate that aids densification duringgranulation (where wet granulation is employed) and therefore improvesblend flow properties and tablet properties.

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable disintegrants as excipients,particularly for tablet formulations. Suitable disintegrants include,but are not limited to, either individually or in combination, starches,including sodium starch glycolate (e.g., Explotab™ of PenWest) andpregelatinized corn starches (e.g., National™ 1551 of National Starchand Chemical Company, National™ 1550, and Colocorn™ 1500), clays (e.g.,Veegum™ HV of R. T. Vanderbilt), celluloses such as purified cellulose,microcrystalline cellulose, methylcellulose, carboxymethylcellulose andsodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol™of FMC), alginates, crospovidone, and gums such as agar, guar, locustbean, karaya, pectin and tragacanth gums.

Disintegrants may be added at any suitable step during the preparationof the composition, particularly prior to granulation or during alubrication step prior to compression. Such disintegrants, if present,constitute in total about 0.2% to about 30%, preferably about 0.2% toabout 10%, and more preferably about 0.2% to about 5%, of the totalweight of the composition.

Croscarmellose sodium is a preferred disintegrant for tablet or capsuledisintegration, and, if present, preferably constitutes about 0.2% toabout 10%, more preferably about 0.2% to about 7%, and still morepreferably about 0.2% to about 5%, of the total weight of thecomposition. Croscarmellose sodium confers superior intragranulardisintegration capabilities to granulated pharmaceutical compositions ofthe present invention.

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable binding agents or adhesives asexcipients, particularly for tablet formulations. Such binding agentsand adhesives preferably impart sufficient cohesion to the powder beingtableted to allow for normal processing operations such as sizing,lubrication, compression and packaging, but still allow the tablet todisintegrate and the composition to be absorbed upon ingestion. Suchbinding agents may also further prevent or inhibit crystallization orrecrystallization/precipitation of a celecoxib salt of the presentinvention once the salt has been dissolved in a solution. Suitablebinding agents and adhesives include, but are not limited to, eitherindividually or in combination, acacia; tragacanth; sucrose; gelatin;glucose; starches such as, but not limited to, pregelatinized starches(e.g., National™ 1511 and National™ 1500); celluloses such as, but notlimited to, methylcellulose and carmellose sodium (e.g., Tylose™);alginic acid and salts of alginic acid; magnesium aluminum silicate;PEG; guar gum; polysaccharide acids; bentonites; povidone, for examplepovidone K-15, K-30 and K-29/32; polymethacrylates; HPMC;hydroxypropylcellulose (e.g., Klucel™ of Aqualon); and ethylcellulose(e.g., Ethocel™ of the Dow Chemical Company). Such binding agents and/oradhesives, if present, constitute in total about 0.5% to about 25%,preferably about 0.75% to about 15%, and more preferably about 1% toabout 10%, of the total weight of the pharmaceutical composition.

Many of the binding agents are polymers comprising amide, ester, ether,alcohol or ketone groups and, as such, are preferably included inpharmaceutical compositions of the present invention.Polyvinylpyrrolidones such as povidone K-30 are especially preferred.Polymeric binding agents can have varying molecular weight, degrees ofcrosslinking, and grades of polymer. Polymeric binding agents can alsobe copolymers, such as block co-polymers that contain mixtures ofethylene oxide and propylene oxide units. Variation in these units'ratios in a given polymer affects properties and performance. Examplesof block co-polymers with varying compositions of block units arePoloxamer 188 and Poloxamer 237 (BASF Corporation).

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable wetting agents as excipients. Suchwetting agents are preferably selected to maintain the celecoxib inclose association with water, a condition that is believed to improvebioavailability of the composition. Such wetting agents can also beuseful in solubilizing or increasing the solubility of metal salts ofcelecoxib.

Non-limiting examples of surfactants that can be used as wetting agents(not necessarily as the precipitation retardant) in pharmaceuticalcompositions of the invention include quatemary ammonium compounds, forexample benzalkonium chloride, benzethonium chloride and cetylpyridiniumchloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenylethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9,poloxamers (polyoxyethylene and polyoxypropylene block copolymers),polyoxyethylene fatty acid glycerides and oils, for examplepolyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether,polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate, polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefosse), sodium lauryl sulfate, fatty acids and salts thereof, forexample oleic acid, sodium oleate and triethanolamine oleate, glycerylfatty acid esters, for example glyceryl monostearate, sorbitan esters,for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate, tyloxapol, and mixturesthereof. Such wetting agents, if present, constitute in total about0.25% to about 15%, preferably about 0.4% to about 10%, and morepreferably about 0.5% to about 5%, of the total weight of thepharmaceutical composition.

Wetting agents that are anionic surfactants are preferred. Sodium laurylsulfate is a particularly preferred wetting agent. Sodium laurylsulfate, if present, constitutes about 0.25% to about 7%, morepreferably about 0.4% to about 4%, and still more preferably about 0.5%to about 2%, of the total weight of the pharmaceutical composition.

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable lubricants (including anti-adherentsand/or glidants) as excipients. Suitable lubricants include, but are notlimited to, either individually or in combination, glyceryl behapate(e.g., Compritol™ 888 of Gattefosse); stearic acid and salts thereof,including magnesium, calcium and sodium stearates; hydrogenatedvegetable oils (e.g., Sterotex™ of Abitec); colloidal silica; talc;waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate;sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™6000 of the Dow Chemical Company); sodium oleate; sodium lauryl sulfate;and magnesium lauryl sulfate. Such lubricants, if present, constitute intotal about 0.1% to about 10%, preferably about 0.2% to about 8%, andmore preferably about 0.25% to about 5%, of the total weight of thepharmaceutical composition.

Magnesium stearate is a preferred lubricant used, for example, to reducefriction between the equipment and granulated mixture during compressionof tablet formulations.

Suitable anti-adherents include, but are not limited to, talc,cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates.Talc is a preferred anti-adherent or glidant used, for example, toreduce formulation sticking to equipment surfaces and also to reducestatic in the blend. Talc, if present, constitutes about 0.1% to about10%, more preferably about 0.25% to about 5%, and still more preferablyabout 0.5% to about 2%, of the total weight of the pharmaceuticalcomposition.

Glidants can be used to promote powder flow of a solid formulation.Suitable glidants include, but are not limited to, colloidal silicondioxide, starch, talc, tribasic calcium phosphate, powdered celluloseand magnesium trisilicate. Colloidal silicon dioxide is particularlypreferred. Other excipients such as colorants, flavors and sweetenersare known in the pharmaceutical arts and can be used in pharmaceuticalcompositions of the present invention. Tablets can be coated, forexample with an enteric coating, or uncoated. Compositions of theinvention can further comprise, for example, buffering agents.

Optionally, one or more effervescent agents can be used as disintegrantsand/or to enhance organoleptic properties of pharmaceutical compositionsof the invention. When present in pharmaceutical compositions of theinvention to promote dosage form disintegration, one or moreeffervescent agents are preferably present in a total amount of about30% to about 75%, and preferably about 45% to about 70%, for exampleabout 60%, by weight of the pharmaceutical composition.

According to a particularly preferred embodiment of the invention, aneffervescent agent, present in a solid dosage form in an amount lessthan that effective to promote disintegration of the dosage form,provides improved dispersion of the celecoxib in an aqueous medium.Without being bound by theory, it is believed that the effervescentagent is effective to accelerate dispersion of celecoxib from the dosageform in the gastrointestinal tract, thereby further enhancing absorptionand rapid onset of therapeutic effect. When present in a pharmaceuticalcomposition of the invention to promote intragastrointestinal dispersionbut not to enhance disintegration, an effervescent agent is preferablypresent in an amount of about 1% to about 20%, more preferably about2.5% to about 15%, and still more preferably about 5% to about 10% byweight of the pharmaceutical composition.

An “effervescent agent” herein is an agent comprising one or morecompounds which, acting together or individually, evolve a gas oncontact with water. The gas evolved is generally oxygen or, mostcommonly, carbon dioxide. Preferred effervescent agents comprise an acidand a base that react in the presence of water to generate carbondioxide gas. Preferably, the base comprises an alkali metal or alkalineearth metal carbonate or bicarbonate and the acid comprises an aliphaticcarboxylic acid.

Non-limiting examples of suitable bases as components of effervescentagents useful in the invention include carbonate salts (e.g., calciumcarbonate), bicarbonate salts (e.g., sodium bicarbonate),sesquicarbonate salts, and mixtures thereof. Calcium carbonate is apreferred base.

Non-limiting examples of suitable acids as components of effervescentagents and/or solid organic acids useful in the invention include citricacid, tartaric acid (as D-, L-, or D/L-tartaric acid), malic acid,maleic acid, funaric acid, adipic acid, succinic acid, acid anhydridesof such acids, acid salts of such acids, and mixtures thereof. Citricacid is a preferred acid.

In a preferred embodiment of the invention, where the effervescent agentcomprises an acid and a base, the weight ratio of the acid to the baseis about 1:100 to about 100:1, more preferably about 1:50 to about 50:1,and still more preferably about 1:10 to about 10:1. In a furtherpreferred embodiment of the invention, where the effervescent agentcomprises an acid and a base, the ratio of the acid to the base isapproximately stoichiometric.

Excipients which solubilize metal salts of celecoxib typically have bothhydrophilic and hydrophobic regions, or are preferably amphiphilic orhave amphiphilic regions. One type of amphiphilic orpartially-amphiphilic excipient comprises an amphiphilic polymer or isan amphiphilic polymer. A specific amphiphilic polymer is a polyalkyleneglycol, which is commonly comprised of ethylene glycol and/or propyleneglycol subunits. Such polyalkylene glycols can be esterified at theirtermini by a carboxylic acid, ester, acid anhyride or other suitablemoiety. Examples of such excipients include poloxamers (symmetric blockcopolymers of ethylene glycol and propylene glycol; e.g., poloxamer237), polyalkyene glycolated esters of tocopherol (including estersformed from a di- or multi-functional carboxylic acid; e.g.,d-alpha-tocopherol polyethylene glycol-1000 succinate), andmacrogolglycerides (formed by alcoholysis of an oil and esterificationof a polyalkylene glycol to produce a mixture of mono-, di- andtri-glycerides and mono- and di-esters; e.g., stearoyl macrogol-32glycerides). Such pharmaceutical compositions are advantageouslyadministered orally.

Pharmaceutical compositions of the present invention can comprise about10% to about 50%, about 25% to about 50%, about 30% to about 45%, orabout 30% to about 35% by weight of a metal salt of celecoxib; about 10%to about 50%, about 25% to about 50%, about 30% to about 45%, or about30% to about 35% by weight of an excipient which inhibits precipitation;and about 5% to about 50%, about 10% to about 40%, about 15% to about35%, or about 30% to about 35% by weight of a binding agent. In oneexample, the weight ratio of the metal salt of celecoxib to theexcipient which inhibits precipitation to binding agent is about 1 to 1to 1.

The resulting formulations described above are both physically andchemically stable. The present invention can be prepared in solid dosageform well in advance (e.g., months) of oral administration without therisk of premature neutralization or precipitation of the API. Liquidsuspensions of celecoxib particles can suffer from a tendency of theparticles to agglomerate and/or increase in size by crystal growth afteronly several minutes of standing. This crystal growth can significantlyreduce the bioavailability and therapeutic effect of the drug.

Solid dosage forms of the invention can be prepared by any suitableprocess, and are not limited to processes described herein. Anillustrative process comprises (i) a step of blending a celecoxib saltof the invention with one or more excipients to form a blend, and (ii) astep of tableting or encapsulating the blend to form tablets orcapsules, respectively.

In a preferred process, solid dosage forms are prepared by a processcomprising (a) a step of blending the celecoxib salt to form a blend,(b) a step of granulating the blend to form a granulate, and (c) a stepof tableting or encapsulating the blend to form tablets or capsulesrespectively. Step (b) can be accomplished by any dry or wet granulationtechnique known in the art. A celecoxib salt is advantageouslygranulated to form particles of about 10 micrometer to about 1000micrometer, about 25 micrometer to about 500 micrometer, or about 50micrometer to about 300 micrometer. More specifically, particles ofabout 100 micrometers in diameter are well suited to yield the desiredtherapeutic effect. One or more diluents, one or more disintegrants andone or more binding agents may be added, for example in the blendingstep, a wetting agent can optionally be added, for example in thegranulating step, and one or more disintegrants may be added aftergranulating but before tableting or encapsulating. A lubricant may beadded before tableting. Blending and granulating can be performedindependently under low or high shear. A process is preferably selectedthat forms a granulate that is uniform in drug content, that readilydisintegrates, that flows with sufficient ease so that weight variationcan be reliably controlled during capsule filling or tableting, and thatis dense enough in bulk so that a batch can be processed in the selectedequipment and individual doses fit into the specified capsules or tabletdies.

In an alternative embodiment, solid dosage forms are prepared by aprocess that includes a spray drying step, wherein a celecoxib salt issuspended with one or more excipients in one or more sprayable liquids,preferably a non-protic (e.g., non-aqueous or non-alcoholic) sprayableliquid, and then is rapidly spray dried over a current of warm air.

A granulate or spray dried powder resulting from any of the aboveillustrative processes can be compressed or molded to prepare tablets orencapsulated to prepare capsules. Conventional tableting andencapsulation techniques known in the art can be employed. Where coatedtablets are desired, conventional coating techniques are suitable.

Excipients for tablet compositions of the invention are preferablyselected to provide a disintegration time of less than about 30 minutes,preferably about 25 minutes or less, more preferably about 20 minutes orless, and still more preferably about 15 minutes or less, in a standarddisintegration assay.

Celecoxib dosage forms of the invention preferably comprise celecoxib ina daily dosage amount of about 10 mg to about 1000 mg, more preferablyabout 50 mg to about 100 mg, about 100 mg to about 150 mg, 150 mg toabout 200 mg, 200 mg to about 250 mg, 250 mg to about 300 mg, 300 mg toabout 350 mg, 350 mg to about 400 mg, 400 mg to about 450 mg 450 mg toabout 500 mg, 500 mg to about 550 mg, 550 mg to about 600 mg, 600 mg toabout 700 mg, and 700 mg to about 800 mg.

Pharmaceutical compositions of the invention comprise one or more orallydeliverable dose units. Each dose unit comprises celecoxib in atherapeutically effective amount that is preferably those listed. Theterm “dose unit” herein means a portion of a pharmaceutical compositionthat contains an amount of a therapeutic or prophylactic agent, in thepresent case celecoxib, suitable for a single oral administration toprovide a therapeutic effect. Typically one dose unit, or a smallplurality (up to about 4) of dose units, in a single administrationprovides a dose comprising a sufficient amount of the agent to result inthe desired effect. Administration of such doses can be repeated asrequired, typically at a dosage frequency of 1, 2, 3, or 4 times perday.

It will be understood that a therapeutically effective amount ofcelecoxib for a subject is dependent inter alia on the body weight ofthe subject. A “subject” to which a celecoxib salt or a pharmaceuticalcomposition thereof can be administered includes a human subject ofeither sex and of any age, and also includes any nonhuman animal,particularly a warm-blooded animal, more particularly a domestic orcompanion animal, illustratively a cat, dog or horse. When the subjectis a child or a small animal (e.g., a dog), for example, an amount ofcelecoxib (measured as the neutral form of celecoxib, that is, notincluding counterions in a salt or water in a hydrate) relatively low inthe preferred range of about 10 mg to about 1000 mg is likely to provideblood serum concentrations consistent with therapeutic effectiveness.Where the subject is an adult human or a large animal (e.g., a horse),achievement of such blood serum concentrations of celecoxib is likely torequire dose units containing a relatively greater amount of celecoxib.

Typical dose units in a pharmaceutical composition of the inventioncontain about 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250,300, 350, or 400 mg of celecoxib. For an adult human, a therapeuticallyeffective amount of celecoxib per dose unit in a composition of thepresent invention is typically about 50 mg to about 400 mg. Especiallypreferred amounts of celecoxib per dose unit are about 100 mg to about200 mg, for example about 100 mg or about 200 mg. Other doses that arenot in current use for CELEBREX may become preferred, if thebioavailability is changed with a novel formulation. For instance, 300mg may become a preferred dose for certain indications.

A dose unit containing a particular amount of celecoxib can be selectedto accommodate any desired frequency of administration used to achieve adesired daily dosage. The daily dosage and frequency of administration,and therefore the selection of appropriate dose unit, depends on avariety of factors, including the age, weight, sex and medical conditionof the subject, and the nature and severity of the condition ordisorder, and thus may vary widely.

For pain management, pharmaceutical compositions of the presentinvention can be used to provide a daily dosage of celecoxib of about 50mg to about 1000 mg, preferably about 100 mg to about 600 mg, morepreferably about 150 mg to about 500 mg, and still more preferably about175 mg to about 400 mg, for example about 200 mg. A daily dose ofcelecoxib of about 0.7 to about 13 mg/kg body weight, preferably about1.3 to about 8 mg/kg body weight, more preferably about 2 to about 6.7mg/kg body weight, and still more preferably about 2.3 to about 5.3mg/kg body weight, for example about 2.7 mg/kg body weight, is generallyappropriate when administered in a pharmaceutical composition of theinvention. The daily dose can be administered in one to about four dosesper day. Administration at a rate of one 50 mg dose unit four times aday, one 100 mg dose unit or two 50 mg dose units twice a day, or one200 mg dose unit, two 100 mg dose units or four 50 mg dose units once aday is preferred.

The term “oral administration” herein includes any form of delivery of atherapeutic agent or a composition thereof to a subject wherein theagent or composition is placed in the mouth of the subject, whether ornot the agent or composition is immediately swallowed, although each areembodiments of the invention. Thus, “oral administration” includesbuccal and sublingual as well as esophageal administration. Absorptionof the agent can occur in any part or parts of the gastrointestinaltract including the mouth, esophagus, stomach, duodenum, ileum andcolon. The term “orally deliverable” herein means suitable for oraladministration.

In a particular embodiment of the present invention, multiple pelletscan be incorporated into the formulation, each with a distinct coatingthickness. This will allow each pellet to dissolve at an exclusive,predetermined time interval following administration. The result is anincreased duration of the desired therapeutic effect. Such acontrolled-release (CR) formulation can reduce the frequency at which apharmaceutical must be administered to a patient, thereby decreasing thetotal amount of drug intake. Improvements such as reduced side effects,reduced drug accumulation, and reduced fluctuations in blood serum levelare some advantages of controlled-release formulations. A furtherembodiment allows the formulation to include more than one therapeuticagent. Pellets of two or more APIs can be incorporated, each withdistinct coating thicknesses, thereby resulting in binary, tertiary, orhigher order pharmaceuticals (Cherng-ju Kim, Controlled Release DosageForm Design).

An important aspect of the administration of drugs in conventional formsis the fluctuation between high and low blood serum concentration of thedrug in the period between the administration of two successive doses.In fact, if the drug is too rapidly absorbed, excessive plasma levelsmay be attained, leading to undesirable and even toxic side effects. Onthe other hand, drugs possessing a short half-life are eliminated toorapidly and require therefore frequent administrations. In both casesthe patient must be careful because particular attention and constancyin the administration is required during therapy and such conditionscannot always be easily obtained. Many efforts have been made toformulate pharmaceutical preparations able to protract in time theactivity of the drug in the body at optimum plasma levels, reducing thenumber of administrations and thus improving the response of the patientto the treatment.

The preparation of pharnaceutical compositions intended to supply agradual and controlled release in time of the active ingredient is wellknown in the pharmaceutical technology field. Systems are knowncomprising tablets, capsules, microcapsules, microspheres andformulations in general, in which the active ingredient is releasedgradually by various means including the following. Particles containingthe API can be coated with individual specific external coatings so thatthe release of active medicament from the inner core is separated bysequential intervals. The number of defined pulses of drug released by aformulation can range from about 1 to about 10, or more specificallyfrom about 1 to about 5. When applicable, a drug-free lag time can beinstituted before the release of first dosage of the active medicament.This drug-free lag time is accomplished by delaying the firstpulse-release.

The dosage forms of the present invention may optionally be coated withone or more materials suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release, e.g., whenexposed to gastrointestinal fluid. A pH-dependent coating serves torelease the API in desired areas of the gastrointestinal (GI) tract,e.g., the stomach or small intestine, such that an absorption profile isprovided which is capable of providing at least about eight hours andpreferably about twelve hours to up to about twenty-four hours ofanalgesia to a patient. When a pH-independent coating is desired, thecoating is designed to achieve optimal release regardless of pH-changesin the environmental fluid, e.g., the GI tract. It is also possible toformulate compositions which release a portion of the dose in onedesired area of the GI tract, e.g., the stomach, and release theremainder of the dose in another area of the GI tract, e.g., the smallintestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the API is coated with a hydrophobicmaterial selected from (i) an alkylcellulose; (ii) an acrylic polymer;or (iii) mixtures thereof. The coating may be applied in the form of anorganic or aqueous solution or dispersion. The coating may be applied toobtain a weight gain from about 2 to about 25% of the substrate in orderto obtain a desired sustained release profile. Coatings derived fromaqueous dispersions are described in detail in U.S. Pat. Nos. 5,273,760and 5,286,493, and are hereby incorporated by reference in theirentirety. Other examples of sustained release formulations and coatingswhich may be used in accordance with the present invention include U.S.Pat. Nos. 5,324,351, 5,356,467, and 5,472,712, also hereby incorporatedby reference in their entirety.

Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to theinvention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the controlled release coating is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate co-polymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers arc well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Rohm Tech, Inc.There are several different types of Eudragit®. For example, Eudragit® Eis an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit® L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit® S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit® RL andEudragit® RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit® RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain a sustainedrelease formulation having a desirable dissolution profile. Desirablesustained release formulations may be obtained, for instance, from aretardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Of course, oneskilled in the art will recognize that other acrylic polymers may alsobe used, such as, for example, Eudragit® L.

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent by weight of the film-former. Concentration of theplasticizer, however, can only be properly determined after carefulexperimentation with the particular coating solution and method ofapplication.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate, tributyl citrate, dibutyl phthalate, andpossibly 1,2-propylene glycol. Other plasticizers which have proved tobe suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talcreduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

When a hydrophobic material is used to coat inert pharmaceutical beads,a plurality of the resultant solid controlled release beads maythereafter be placed in a gelatin capsule in an amount sufficient toprovide an effective controlled release dose when ingested and contactedby an environmental fluid, e.g., gastric fluid or dissolution media.

The controlled release bead formulations of the present invention slowlyrelease the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. The controlledrelease profile of the formulations of the invention can be altered, forexample, by varying the amount of overcoating with the hydrophobicmaterial, altering the manner in which the plasticizer is added to thehydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc. The dissolutionprofile of the ultimate product may also be modified, for example, byincreasing or decreasing the thickness of the retardant coating.

Spheroids or beads coated with a therapeutically active agent areprepared, e.g., by dissolving the therapeutically active agent in waterand then spraying the solution onto a substrate, for example, using aWuster insert. Optionally, additional ingredients are also added priorto coating the beads in order to assist the binding of the API to thebeads, and/or to color the solution, etc. For example, a product whichincludes hydroxypropyhmethylcellulose, etc. with or without colorant(e.g., Opadry®, commercially available from Colorcon, Inc.) may be addedto the solution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the therapeutically active agent from the hydrophobiccontrolled release coating. An example of a suitable barrier agent isone which comprises hydroxypropylmethylcellulose. However, anyfilm-former known in the art may be used. It is preferred that thebarrier agent does not affect the dissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

Plasticized hydrophobic material may be applied onto the substratecomprising the therapeutically active agent by spraying using anysuitable spray equipment known in the art. In a preferred method, aWurster fluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid therapeutically active agent when the coated substrate is exposedto aqueous solutions, e.g. gastric fluid, is preferably applied, takinginto account the physical characteristics of the therapeutically activeagent, the manner of incorporation of the plasticizer, etc. Aftercoating with the hydrophobic material, a further overcoat of afilm-former, such as Opadry®, is optionally applied to the beads. Thisovercoat is provided, if at all, in order to substantially reduceagglomeration of the beads.

The release of the therapeutically active agent from the controlledrelease formulation of the present invention can be further influenced,i.e., adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The sustained release coatings of the present invention can also includeerosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain. Therelease-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of whichare hereby incorporated by reference). The passageway can have any shapesuch as round, triangular, square, elliptical, irregular, etc.

The present invention may include dual-release compositions whereby acelecoxib salt is formulated so as to contain both a fast actingcomponent and a sustained release component of drug delivery. Thisformulation allows for both relatively fast and prolonged therapeuticeffects while minimizing administration frequency. Dual-releasecompositions are further described in WO 01/45706 A1, the contents ofwhich are herein incorporated by reference in their entirety.

A variety of known controlled- or extended-release dosage forms,formulations, and devices can be adapted for use with the celecoxibsalts and compositions of the invention. Examples include, but are notlimited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 B1;each of which is incorporated herein by reference. These dosage formscan be used to provide slow or controlled-release of one or more activeingredients using, for example, hydroxypropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems (such asOROS® (Alza Corporation, Mountain View, Calif. USA)), multilayercoatings, microparticles, liposomes, or microspheres or a combinationthereof to provide the desired release profile in varying proportions.Additionally, ion exchange materials can be used to prepare immobilized,adsorbed salt forms of celecoxib and thus effect controlled delivery ofthe drug. Examples of specific anion exchangers include, but are notlimited to, Duolite® A568 and Duolite® AP143 (Rohm & Haas, Spring House,Pa. USA).

One embodiment of the invention encompasses a unit dosage form whichcomprises a pharmaceutically acceptable salt of celecoxib (e.g., asodium, potassium, or lithium salt), or a polymorph, solvate, hydrate,dehydrate, co-crystal, anhydrous, or amorphous form thereof, and one ormore pharmaceutically acceptable excipients or diluents, wherein thepharmaceutical composition or dosage form is formulated forcontrolled-release. Specific dosage forms utilize an osmotic drugdelivery system.

A particular and well-known osmotic drug delivery system is referred toas OROS® (Alza Corporation, Mountain View, Calif. USA). This technologycan readily be adapted for the delivery of compounds and compositions ofthe invention. Various aspects of the technology are disclosed in U.S.Pat. Nos. 6,375,978 B1; 6,368,626 B1; 6,342,249 B1; 6,333,050 B2;6,287,295 B1; 6,283,953 B1; 6,270,787 B1; 6,245,357 B1; and 6,132,420;each of which is incorporated herein by reference. Specific adaptationsof OROS® that can be used to administer compounds and compositions ofthe invention include, but are not limited to, the OROS® Push-Pull™,Delayed Push-Pull™, Multi-Layer Push-Pull™, and Push-Stick™ Systems, allof which are well known. See, e.g., http://www.alza.com. AdditionalOROS® systems that can be used for the controlled oral delivery ofcompounds and compositions of the invention include OROS®-CT andL-OROS®. Id.; see also, Delivery Times, vol. II, issue II (AlzaCorporation).

Conventional OROS® oral dosage forms are made by compressing a drugpowder (e.g., celecoxib salt) into a hard tablet, coating the tabletwith cellulose derivatives to form a semi-permeable membrane, and thendrilling an orifice in the coating (e.g., with a laser). Kim, Cherng-ju,Controlled Release Dosage Form Design, 231-238 (Technomic Publishing,Lancaster, Pa.: 2000). The advantage of such dosage forms is that thedelivery rate of the drug is not influenced by physiological orexperimental conditions. Even a drug with a pH-dependent solubility canbe delivered at a constant rate regardless of the pH of the deliverymedium. But because these advantages are provided by a build-up ofosmotic pressure within the dosage form after administration,conventional OROS® drug delivery systems cannot be used to effectivelydeliver drugs with low water solubility. Because celecoxib salts andcomplexes of this invention (e.g., celecoxib sodium) are far moresoluble in water than celecoxib itself, they are well suited forosmotic-based delivery to patients. This invention does, however,encompass the incorporation of celecoxib, and non-salt isomers andisomeric mixtures thereof, into OROS® dosage forms.

A specific dosage form of the invention comprises: a wall defining acavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a dry orsubstantially dry state drug layer located within the cavity adjacent tothe exit orifice and in direct or indirect contacting relationship withthe expandable layer; and a flow-promoting layer interposed between theinner surface of the wall and at least the external surface of the druglayer located within the cavity, wherein the drug layer comprises a saltof celecoxib, or a polymorph, solvate, hydrate, dehydrate, co-crystal,anhydrous, or amorphous form thereof. See U.S. Pat. No. 6,368,626, theentirety of which is incorporated herein by reference.

Another specific dosage form of the invention comprises: a wall defininga cavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a drug layerlocated within the cavity adjacent the exit orifice and in direct orindirect contacting relationship with the expandable layer; the druglayer comprising a liquid, active agent formulation absorbed in porousparticles, the porous particles being adapted to resist compactionforces sufficient to form a compacted drug layer without significantexudation of the liquid, active agent formulation, the dosage formoptionally having a placebo layer between the exit orifice and the druglayer, wherein the active agent formulation comprises a salt ofcelecoxib, or a polymorph, solvate, hydrate, dehydrate, co-crystal,anhydrous, or amorphous form thereof. See U.S. Pat. No. 6,342,249, theentirety of which is incorporated herein by reference.

Celecoxib compositions useful in methods of the present invention can beused in combination therapies with opioids and other analgesics. Thecompound to be administered in combination with a celecoxib compositionuseful in methods of the invention can be formulated separately fromsaid composition or co-formulated with said composition. Where acelecoxib composition is co-formulated with a second drug, for examplean opioid drug, the second drug can be formulated in immediate-release,rapid-onset, sustained-release or dual-release form. In a specificembodiment of the present invention, celecoxib can be combined with ananti-platelet drug for example, but not limited to, tirofiban, aspirin,dipyridamole, anagrelide, epoprostenol, eptifibatide, clopidogrel,cilostazol, abciximab, or ticlopidine.

In another embodiment of the present invention, a formulation comprisesa celecoxib salt (e.g., celecoxib sodium salt) and the free acid form.This combination allows for both a fast onset and a delayed responsefollowing administration to a subject. In another embodiment, thecombination of a celecoxib salt and the free acid also comprises anyone, any two, any three, any four, or any five or more excipients listedherein (e.g., precipitation retardants, enhancers, etc.).

Pharmaceutical compositions of the invention are useful in treatment andprevention of a very wide range of disorders mediated by COX-2,including but not restricted to disorders characterized by inflammation,pain and/or fever. Such pharmaceutical compositions are especiallyuseful as anti-inflammatory agents, such as in treatment of arthritis,with the additional benefit of having significantly less harmful sideeffects than compositions of conventional non-steroidalanti-inflammatory drugs (NSAIDs) that lack selectivity for COX-2 overCOX-1. In particular, pharmaceutical compositions of the invention havereduced the potential for gastrointestinal toxicity and gastrointestinalirritation including upper gastrointestinal ulceration and bleeding,reduced potential for renal side effects such as reduction in renalfunction leading to fluid retention and exacerbation of hypertension,reduced effect on bleeding times including inhibition of plateletfunction, and possibly a lessened ability to induce asthma attacks inaspirin-sensitive asthmatic subjects, by comparison with compositions ofconventional NSAIDs. Thus compositions of the invention are particularlyuseful as an alternative to conventional NSAIDs where such NSAIDs arecontraindicated, for example in subjects with peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis or with arecurrent history of gastrointestinal lesions; gastrointestinalbleeding, coagulation disorders including anemia such ashypoprothrombinemia, hemophilia or other bleeding problems, kidneydisease, or in subjects prior to surgery or subjects takinganticoagulants.

Contemplated pharmaceutical compositions are useful to treat a varietyof arthritic disorders, including but not limited to rheumatoidarthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,systemic lupus erythematosus and juvenile arthritis.

Such pharmaceutical compositions are useful in treatment of asthma,bronchitis, menstrual cramps, preterm labor, tendonitis, bursitis,allergic neuritis, cytomegalovirus infectivity, apoptosis includingHIV-induced apoptosis, lumbago, liver disease including hepatitis,skin-related conditions such as psoriasis, eczema, acne, burns,dermatitis and ultraviolet radiation damage including sunburn, andpost-operative inflammation including that following ophthalmic surgerysuch as cataract surgery or refractive surgery.

Pharmaceutical compositions of the present invention are useful to treatgastrointestinal conditions such as, but not limited to, inflammatorybowel disease, Crohn's disease, gastritis, irritable bowel syndrome andulcerative colitis.

Such pharmaceutical compositions are useful in treating inflammation insuch diseases as migraine headaches, periarteritis nodosa, thyroiditis,aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type Idiabetes, neuromuscular junction disease including myasthenia gravis,white matter disease including multiple sclerosis, sarcoidosis,nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,nephritis, hypersensitivity, swelling occurring after injury includingbrain edema, myocardial ischemia, and the like.

In addition, these pharmaceutical compositions are useful in treatmentof ophthalmic diseases, such as retinitis, conjunctivitis,retinopathies, uveitis, ocular photophobia, and of acute injury to theeye tissue.

Also, such pharmaceutical compositions are useful in treatment ofpulmonary inflammation, such as that associated with viral infectionsand cystic fibrosis, and in bone resorption such as that associated withosteoporosis.

The pharmaceutical compositions are useful for treatment of certaincentral nervous system disorders, such as cortical dementias includingAlzheimer's disease, neurodegeneration, and central nervous systemdamage resulting from stroke, ischemia and trauma. The term “treatment”in the present context includes partial or total inhibition ofdementias, including Alzheimer's disease, vascular dementia,multi-infarct dementia, pre-senile dementia, alcoholic dementia andsenile dementia.

Such pharmaceutical compositions are useful in treatment of allergicrhinitis, respiratory distress syndrome, endotoxin shock syndrome andliver disease.

Further, pharmaceutical compositions of the present invention are usefulin treatment of pain, including but not limited to postoperative pain,dental pain, muscular pain, and pain resulting from cancer. For example,such compositions are useful for relief of pain, fever and inflammationin a variety of conditions including rheumatic fever, influenza andother viral infections including common cold, low back and neck pain,dysmenorrhea, headache, toothache, sprains and strains, myositis,neuralgia, synovitis, arthritis, including rheumatoid arthritis,degenerative joint diseases (osteoarthritis), gout and ankylosingspondylitis, bursitis, burns, and trauma following surgical and dentalprocedures.

The present invention is further directed to a therapeutic method oftreating a condition or disorder where treatment with a COX-2 inhibitorydrug is indicated, the method comprising oral administration of apharmaceutical composition of the invention to a subject in needthereof. The dosage regimen to prevent, give relief from, or amelioratethe condition or disorder preferably corresponds to once-a-day ortwice-a-day treatment, but can be modified in accordance with a varietyof factors. These include the type, age, weight, sex, diet and medicalcondition of the subject and the nature and severity of the disorder.Thus, the dosage regimen actually employed can vary widely and cantherefore deviate from the preferred dosage regimens set forth above.The present pharmaceutical compositions can be used in combination withother therapies or therapeutic agents, including but not limited to,therapies with opioids and other analgesics, including narcoticanalgesics, Mu receptor antagonists, Kappa receptor antagonists,non-narcotic (i.e. non-addictive) analgesics, monoamine uptakeinhibitors, adenosine regulating agents, cannabinoid derivatives, GABAactive agents, norexin neuropeptide modulators, Substance P antagonists,neurokinin-1 receptor antagonists and sodium channel blockers, amongothers. Preferred combination therapies comprise use of a composition ofthe invention with one or more compounds selected from aceclofenac,acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol,acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine,alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin,alphaprodine, aluminum bis(acetylsalicylate), amfenac,aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline,aminopropylon, aminopyrine, amixetrine, ammonium salicylate,ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antipyrinesalicylate, antrafenine, apazone, bendazac, benorylate, benoxaprofen,benzpiperylon, benzydamine, benzylmorphine, bermoprofen, bezitramide,alpha-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acidacetate, bromosaligenin, bucetin, bucloxic acid, bucolome, bufexamac,bumadizon, buprenorphine, butacetin, butibufen, butophanol, calciumacetylsalicylate, carbamazepine, carbiphene, carprofen, carsalam,chlorobutanol, chlorthenoxazin, choline salicylate, cinchophen,cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin,clopirac, clove, codeine, codeine methyl bromide, codeine phosphate,codeine sulfate, cropropamide, crotethamide, desomorphine, dexoxadrol,dextromoramide, dezocine, diampromide, diclofenac sodium, difenamizole,difenpiramide, diflunisal, dihydrocodeine, dihydrocodeinone enolacetate, dihydromorphine, dihydroxyaluminum acetylsalicylate,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, diprocetyl, dipyrone, ditazol, droxicam, emorfazone,enfenamic acid, epirizole, eptazocine, etersalate, ethenzamide,ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine,etodolac, etofenamate, etonitazene, eugenol, felbinac, fenbufen,fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol,feprazone, floctafenine, flufenamic acid, flunoxaprofen, fluoresone,flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid,glafenine, glucametacin, glycol salicylate, guaiazulene, hydrocodone,hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam,imidazole salicylate, indomethacin, indoprofen, isofezolac, isoladol,isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen,ketorolac, p-lactophenetide, lefetamine, levorphanol, lofentanil,lonazolac, lomoxicam, loxoprofen, lysine acetylsalicylate, magnesiumacetylsalicylate, meclofenamic acid, mefenamic acid, meperidine,meptazinol, mesalamine, metazocine, methadone hydrochloride,methotrimeprazine, metiazinic acid, metofoline, metopon, modafinil,mofebutazone, mofezolac, morazone, morphine, morphine hydrochloride,morphine sulfate, morpholine salicylate, myrophine, nabumetone,nalbuphine, 1-naphthyl salicylate, naproxen, narceine, nefopam,nicomorphine, nifenazone, niflumic acid, nimesulide,5′-nitro-2′-propoxyacetanilide, norlevorphanol, normethadone,normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine,oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretum,paranyline, parsahnide, pentazocine, perisoxal, phenacetin, phenadoxone,phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine,phenopyrazone, phenyl acetylsalicylate, phenylbutazone, phenylsalicylate, phenyramidol, piketoprofen, piminodine, pipebuzone,piperylone, piprofen, pirazolac, piritramide, piroxicam, pranoprofen,proglumetacin, proheptazine, promedol, propacetamol, propiram,propoxyphene, propyphenazone, proquazone, protizinic acid, ramifenazone,remifentanil, rimazolium metilsulfate, salacetamide, salicin,salicylamide, salicylamide o-acetic acid, salicylsulfuric acid,salsalte, salverine, simetride, sodium salicylate, sufentanil,sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone,talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine,thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine,tolfenamic acid, tolmetin, topiramate, tramadol, tropesin, viminol,xenbucin, ximoprofen, zaltoprofen and zomepirac (see The Merck Index,12th Edition, Therapeutic Category and Biological Activity Index, ed. S.Budavari (1996), pp. Ther-2 to Ther-3 and Ther-12 (Analgesic (D)ental),Analgesic (Narcotic), Analgesic (Non-narcotic), Anti-inflammatory(Non-steroidal)).

Pharmaceutical compositions of the present invention are useful fortreating and preventing inflammation-related cardiovascular disorders,including vascular diseases, coronary artery disease, aneurysm, vascularrejection, arteriosclerosis, atherosclerosis including cardiactransplant atherosclerosis, myocardial infarction, embolism, stroke,thrombosis including venous thrombosis, angina including unstableangina, coronary plaque inflammation, bacterial-induced inflammationincluding Chlamydia-induced inflammation, viral induced inflammation,and inflammation associated with surgical procedures such as vasculargrafting including coronary artery bypass surgery, revascularizationprocedures including angioplasty, stent placement, endarterectomy, orother invasive procedures involving arteries, veins and capillaries.

These pharmaceutical compositions are also useful in treatment ofangiogenesis-related disorders in a subject, for example to inhibittumor angiogenesis. Such pharmaceutical compositions are useful intreatment of neoplasia, including metastasis; ophthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, macular degeneration, retrolentalfibroplasia and neovascular glaucoma; ulcerative diseases such asgastric ulcer; pathological, but non-malignant, conditions such ashemangiomas, including infantile hemaginomas, angiofibroma of thenasopharynx and avascular necrosis of bone; and disorders of the femalereproductive system such as endometriosis.

Moreover, pharmaceutical compositions of the present invention areuseful in prevention and treatment of benign and malignant tumors andneoplasia including cancer, such as colorectal cancer, brain cancer,bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma)such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancersuch as lip cancer, mouth cancer, esophageal cancer, small bowel cancer,stomach cancer, colon cancer, liver cancer, bladder cancer, pancreaticcancer, ovarian cancer, cervical cancer, lung cancer, breast cancer,skin cancer such as squamous cell and basal cell cancers, prostatecancer, renal cell carcinoma, and other known cancers that effectepithelial cells throughout the body. Neoplasias for which compositionsof the invention are contemplated to be particularly useful aregastrointestinal cancer, Barrett's esophagus, liver cancer, bladdercancer, pancreatic cancer, ovarian cancer, prostate cancer, cervicalcancer, lung cancer, breast cancer and skin cancer. Such pharmaceuticalcompositions can also be used to treat fibrosis that occurs withradiation therapy. These pharmaceutical compositions can be used totreat subjects having adenomatous polyps, including those with familialadenomatous polyposis (FAP). Additionally, pharmaceutical compositionsof the present invention can be used to prevent polyps from forming insubjects at risk of FAP.

Also, the pharmaceutical compositions inhibit prostanoid-induced smoothmuscle contraction by inhibiting synthesis of contractile prostanoidsand hence can be of use in treatment of dysmenorrhea, premature labor,asthma and eosinophil-related disorders. They also can be of use fordecreasing bone loss particularly in postmenopausal women (i.e.,treatment of osteoporosis), and for treatment of glaucoma.

Preferred uses for pharmaceutical compositions of the invention are fortreatment of rheumatoid arthritis and osteoarthritis, for painmanagement generally (particularly post-oral surgery pain, post-generalsurgery pain, post-orthopedic surgery pain, and acute flares ofosteoarthritis), for treatment of Alzheimer's disease, and for coloncancer chemoprevention. A particular preferred use is for rapid painmanagement, such as when a celecoxib salt or a pharmaceuticalcomposition thereof is effective in treating pain within about 30minutes or less.

Besides being useful for human treatment, pharmaceutical compositions ofthe invention are useful for veterinary treatment of companion animals,exotic animals, farm animals, and the like, particularly mammals. Moreparticularly, pharmaceutical compositions of the invention are usefulfor treatment of COX-2 mediated disorders in horses, dogs, and cats.

EXEMPLIFICATION

Below are standard procedures for acquiring Raman, PXRD, DSC and TGAdata herein. These procedures will be followed for each respectivemethod of analysis herein unless otherwise indicated.

Procedure for Raman Acquisition

Acquisition

The sample was either left in the glass vial in which it was processedor an aliquot of the sample was transferred to a glass slide. The glassvial or slide was positioned in the sample chamber. The measurement wasmade using an Almega™ Dispersive Raman (Almega™ Dispersive Raman,Thermo-Nicolet, 5225 Verona Road, Madison, Wis. 53711-4495) systemfitted with a 785 nm laser source. The sample was manually brought intofocus using the microscope portion of the apparatus with a 10× powerobjective (unless otherwise noted), thus directing the laser onto thesurface of the sample. The spectrum was acquired using the parametersoutlined in Table 1. (Exposure times and number of exposures may vary;changes to parameters will be indicated for each acquisition.) Unlessotherwise noted, all Raman scattering peaks are ±5 cm⁻¹. TABLE 1 RamanSpectral acquisition parameters Parameter Setting Used Exposure time (s)2.0 Number of exposures 10 Laser source wavelength (nm) 785 Laser power(%) 100 Aperture shape pin hole Aperture size (um) 100 Spectral range(cm⁻¹) 104-3428 Grating position Single Temperature at acquisition 24.0(degrees C.)Procedure for Powder X-Ray Diffraction (PXRD)

All powder x-ray diffraction patterns were obtained using the D/MaxRapid X-ray Diffractometer (D/Max Rapid, Contact Rigaku/MSC, 9009 NewTrails Drive, The Woodlands, Tex., USA 77381-5209) equipped with acopper source (Cu/K₆₀ 1.5406 angstroms), manual x-y stage, and 0.3 mmcollimator (unless otherwise indicated). The sample was loaded into a0.3 mm boron rich glass capillary tube (e.g., Charles Supper Company, 15Tech Circle, Natick, Mass. 01760-1024) by sectioning off one end of thetube and tapping the open, sectioned end into a bed of the powderedsample or into the sediment of a slurried precipitate. Note, precipitatecan be amorphous or crystalline. The loaded capillary was mounted in aholder that was secured into the x-y stage. A diffractogram was acquired(e.g., Control software: RINT Rapid Control Software, Rigaku Rapid/XRD,version 1.0.0, © 1999 Rigaku Co.) under ambient conditions at a powersetting of 46 kV at 40 mA in reflection mode, while oscillating aboutthe omega-axis from 0-5 degrees at 1 degree/s and spinning about thephi-axis at 2 degrees/s. The exposure time was 15 minutes unlessotherwise specified. The diffractogram obtained was integrated over2-theta from 2-60 degrees and chi (1 segment) from 0-360 degrees at astep size of 0.02 degrees using the cyllnt utility in the RINT Rapiddisplay software (Analysis software: RINT Rapid display software,version 1.18, Rigaku/MSC.) provided by Rigaku with the instrument. Thedark counts value was set to 8 as per the system calibration (Systemset-up and calibration by Rigaku); normalization was set to average; theomega offset was set to 180°; and no chi or phi offsets were used forthe integration. The analysis software JADE XRD Pattern Processing,versions 5.0 and 6.0 (⁸1995-2002, Materials Data, Inc.) was also used.

The relative intensity of peaks in a diffractogram is not necessarily alimitation of the PXRD pattern because peak intensity can vary fromsample to sample, e.g., due to crystalline impurities. Further, theangles of each peak can vary by about ±0.1 degrees, preferably ±0.05.The entire pattern or most of the pattern peaks may also shift by about±0.1 degree due to differences in calibration, settings, and othervariations from instrument to instrument and from operator to operator.The above limitations result in a PXRD error of ±0.2 degrees 2-theta foreach diffraction peak.

Procedure for Differential Scanning Calorimetry (DSC)

An aliquot of the sample was weighed into an aluminum sample pan. (e.g.,Pan part #900786.091; lid part #900779.901; TA Instruments, 109 LukensDrive, New Castle, Del. 19720) The sample pan was sealed either bycrimping for dry samples or press fitting for wet samples (e.g.,hydrated or solvated samples). The sample pan was loaded into theapparatus (DSC: Q1000 Differential Scanning Calorimeter, TA Instruments,109 Lukens Drive, New Castle, Del. 19720), which is equipped with anautosampler, and a thermogram was obtained by individually heating thesample (e.g., Control software: Advantage for QW-Series, version1.0.0.78, Thermal Advantage Release 2.0, © 2001 TA instruments—WaterLLC) at a rate of 10 degrees C./min from T_(min) (typically 20 degreesC.) to T_(max) (typically 300 degrees C.) (Heating rate and temperaturerange may vary, changes to these parameters will be indicated for eachsample) using an empty aluminum pan as a reference. Dry nitrogen (e.g.,Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue, MurrayHill, N.J. 07974-2082) was used as a sample purge gas and was set at aflow rate of 50 mL/min. Thermal transitions were viewed and analyzedusing the analysis software (Analysis Software: Universal Analysis 2000for Windows 95/95/2000/NT, version 3.1E; Build 3.1.0.40, © 1991-2001TAinstruments—Water LLC) provided with the instrument.

Procedure for Thermogravimetric Analysis (TGA)

An aliquot of the sample was transferred into a platinum sample pan.(Pan part #952019.906; TA Instruments, 109 Lukens Drive, New Castle,Del. 19720) The pan was placed on the loading platform and was thenautomatically loaded into the apparatus (TGA: Q500 ThermogravimetricAnalyzer, TA Instruments, 109 Lukens Drive, New Castle, Del. 19720)using the control software (Control software: Advantage for QW-Series,version 1.0.0.78, Thermal Advantage Release 2.0, © 2001 TAinstruments—Water LLC). Thermograms were obtained by individuallyheating the sample at 10 degrees C./min from 25 degrees C. to 300degrees C. (Heating rate and temperature range may vary, changes inparameters will be indicated for each sample) under flowing dry nitrogen(e.g., Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue,Murray Hill, N.J. 07974-2082), with a sample purge flow rate of 60mL/min and a balance purge flow rate of 40 mL/min. Thermal transitions(e.g. weight changes) were viewed and analyzed using the analysissoftware (Analysis Software: Universal Analysis 2000 for Windows95/95/2000/NT, version 3.1E; Build 3.1.0.40, © 1991-2001TAinstruments—Water LLC) provided with the instrument.

EXAMPLE 1

Celecoxib Sodium Salt from Aqueous Solution

To 77.3 mg of commercially-available celecoxib was added 1.0 mLdistilled water, followed by 0.220 mL of 1 M NaOH. The mixture washeated with stirring to 60 degrees C., whereupon an additional 1.0 mLdistilled water was added. Solid NaOH (22 mg) was added, and the solidNaOH and celecoxib dissolved. The mixture was heated again at 60 degreesC. to evaporate water. About 15 mL reagent-grade ethanol was added,while the mixture was stirred and heated at 60 degrees C. with airblowing over the solution. Heating continued until the solution was dry.The resulting material was analyzed by differential scanning calorimetry(DSC), thermogravimetric analysis (TGA), and powder x-ray diffraction(PXRD), the results of which are seen in FIGS. 1-3. The product wasfound to contain about 4.1 equivalents of water per equivalent of salt,although most of all of the water could be contained in the NaOH thatco-precipitated with the salt.

For the DSC analysis, the purge gas used was dry nitrogen, the referencematerial was an empty aluminum pan that was crimped, and the samplepurge was 50 mL/minute. DSC analysis of the sample was performed byplacing 2.594 mg of sample in an aluminum pan with a crimped panclosure. The starting temperature was 20 degrees C. with a heating rateof 10 degrees C./minute, and the ending temperature was 200 degrees C. Areproduction of the resulting DSC analysis is shown in FIG. 1. Thetransitions observed include a melt/dehydration process between about 40and about 70 degrees C., another transition between about 70 and about100 degrees C. possibly resulting from a recrystallization/precipitationevent and a second melt/dehydration transition between about 100 andabout 110 degrees C.

TGA of the sample was performed by placing 2.460 mg of sample in aplatinum pan. The starting temperature was 20 degrees C. with a heatingrate of 10 degrees C./minute, and the ending temperature was 300 degreesC. A reproduction of the resulting TGA analysis is shown in FIG. 2. TheTGA shows a mass loss of about 12.5 percent between about 30 and about50 degrees C., attributed to the loss of about 2.8 equivalents of water.A second mass loss of about 2.5 percent between about 71 and 85 degreesC., attributed to the loss of about 0.5 equivalents of water. Finally, amass loss of about 4.0 percent between about 148 and 170° C. attributedto either the loss of about 1 equivalent of water or some decompositionof the drug compound. The hydration state of the salt can vary dependingon the humidity, temperature and other conditions, as discussed inExamples 24, 25, and 30.

A reproduction of the PXRD pattern for the compound prepared above isshown in FIG. 3. In the diffractogram of FIG. 3, the background has beenremoved. The PXRD pattern has characteristic peaks that can be used tocharacterize the salt comprising any one, or any combination of any two,any three, any four, or any five peaks or any other combination of peaksat a 2-theta angle of FIG. 3 including for example, the peaks at 2.87,6.36, 7.01, 16.72, and 20.83 degrees 2-theta.

EXAMPLE 2

Celecoxib Sodium Salt from 2-Propanol Solution

To 126.3 mg of celecoxib was added a 1.0 mL aliquot of isopropanol, andthe mixture was heated to dissolve the celecoxib. Sodium ethoxide wasadded as a solution (21%) in ethanol (0.124 mL solution, 3.31×10⁻⁴ molsodium ethoxide). An additional 1.0 mL of isopropanol was added. Themixture was stirred to obtain a slurry of white crystalline solids thatappeared as fine birefringent needles by polarized light microscopy.

The slurry was filtered by suction filtration and rinsed with 2 mL ofisopropanol. The solid was allowed to air dry before being gently groundto a powder. The product was analyzed by PXRD, DSC, and TGA as inExample 1, but a 0.5 mm capillary was used to hold the sample in thePXRD experiment. The compound lost 17.37% weight between roomtemperature and 120 degrees C. (See FIG. 101). The DSC thermogram showsa broad endothermic region, which is consistent with a loss of volatilecomponents with increasing temperature (See FIG. 102). The endothermpeaks at 66 degrees C. The PXRD pattern peaks that can be used tocharacterize the salt include any one or combination comprising any two,any three, any four, any five, any six, any seven, any eight, any nine,any ten, any eleven, any twelve, or all thirteen 2-theta angles of 4.09,4.99, 6.51, 7.07, 9.99, 11.59, 16.53, 17.69, 18.47, 19.13, 20.11, 20.95,22.67 degrees, or any one or combination of 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, or 13 peaks of FIG. 62.

EXAMPLE 3

Celecoxib Sodium Salt from Aqueous Solution

Synthesis 1: To a vial was added 29.64 mg celecoxib and 3.00 mL of 1 Msodium hydroxide. The celecoxib dissolved. After a time, celecoxibsodium salt precipitated from solution.

Synthesis 2: To a vial was added 7.10 mg celecoxib and 3.00 mL of 1 Msodium hydroxide. The celecoxib dissolved. Overnight, celecoxib sodiumsalt precipitated and formed white, needle-like crystals.

Synthesis 3: To a vial was added 17.6 mg celecoxib and 10 mL of 1 Msodium hydroxide. The celecoxib dissolved. The vial was placed in abeaker wrapped in aluminum foil and filled with a large tissue forinsulation. The beaker was left and celecoxib sodium salt crystalsformed within about 12-36 hours.

Analysis: The product solids from syntheses 1 and 2 were combined andanalyzed by PXRD, DSC, and TGA as in example 1, but a 0.5 mm capillarywas used to hold the sample in the PXRD experiment. The product salt wasfound to contain about 4 equivalents of water per equivalent of salt,although as stated herein the hydration state of the salt can varydepending on humidity, temperature, and other conditions. TGA showed aweight loss of 14.9 percent as the temperature was increased from roomtemperature to 100 degrees C. at 10 degrees C./min. DSC analysis showeda large endothermic transition at 74±1.0 degrees C. and a second broadand noisy endothermic transition at about 130±5.0 degrees C. The PXRDpattern has peaks that can be used to characterize the salt by includingany one or a combination comprising any two, any three, any four, anyfive, or all six 2-theta angle peaks of 3.6, 8.9, 9.6, 10.8, 11.4, and20.0 degrees.

EXAMPLE 4

Pharmacokinetic Studies in Rats

The sodium salt form (from Example 6) was compared with CELEBREX powderin terms of absorption in rats (FIGS. 4A and 4B).

Pharmacokinetics in male Sprague-Dawley rats after 5 mg/kg oral doses ofthe celecoxib crystal form used in the marketed formulations and thesodium salt form are shown in FIGS. 4A and 4B. Solids were placed insize 9 gelatin capsules (Torpac) and dosed via gavage needle, followedby oral gavage of 1 mL water. CELEBREX granulation was transferred fromcommercial 200 mg capsules. The sodium salt was blended withpolyvinylpyrrolidone (e.g. PovidoneK30) in a 1:4 mixture. The plots areaverages of plasma levels at each of the time points from plasma of 5rats.

The pharmacokinetics at 5 mg/kg doses of the celecoxib sodium saltdemonstrate a faster peak level of the drug in plasma. Early timepointsshow higher levels of celecoxib in plasma from the sodium salt relativeto CELEBREX (in particular, see FIG. 4A).

EXAMPLE 5

Solubility of Celecoxib Sodium Salt in the Presence ofPolyvinylpyrrolidone

Water was added to a 1:4 mixture of celecoxib sodium salt andpolyvinylpyrrolidone (PVP) to obtain a clear solution. The solution wasstable for at least 15 minutes, after which time, crystals of neutralcelecoxib began to form.

Crystalline neutral celecoxib did not dissolve when added to aqueouspolyvinylpyrrolidone or when water was added to a dry blend of neutralcrystalline celecoxib and polyvinylpyrrolidone.

EXAMPLE 6

Preparation of Celecoxib Sodium Salt

The free acid of celecoxib (5.027 g; 13.16 mmol) was suspended in a 1 Maqueous solution of NaOH (13.18 mL; 13.18 mmol). The suspension wasgently heated at 60 degrees C. for 1 minute to dissolve the remainingsolid. The mixture was allowed to cool to room temperature, whichyielded no solid. Further cooling in an ice bath for 1 hour yieldedcrystallization of the product. The resulting suspension was filteredand allowed to air dry.

Characterization of the product has been achieved via TGA, DSC, PXRD,and Raman spectroscopy. The TGA shows a weight loss of 6.67 wt % from 25degrees C. to 105 degrees C. This weight loss indicates some level ofhydration or residual water. The DSC shows a large endotherm centered at100 degrees C. The PXRD pattern has characteristic peaks as shown inFIG. 13A. An intense peak can be seen at 19.85 with other peaks at2-theta angles including but not limited to, 3.57, 10.69, 13.69, 20.43,21.53 and 22.39 degrees. The crystal can be characterized by any one,any two, any three, any four, any five, or all six of the peaks above,or any one or combination of any number of 2-theta s angles of FIG. 13A.Results of Raman spectroscopy can be seen in FIG. 13B. Raman shift(cm⁻¹) peaks occur at positions including, but not limited to, any one,any two, any three, any four, all five of 1617, 1446, 1374, 975 and 800cm⁻¹, or any combinations of 2, 3, 4, 5 or more peaks of FIG. 13B.

EXAMPLE 7

Administration of Celecoxib Compositions to Dogs

The celecoxib salt of Example 6 was administered to dogs and compared toadministration of commercially available celecoxib. Six male beagle dogsaged 2-4 years old and weighing 8-12 kg were food-deprived overnight,but were given water. Each of the dogs was administered 3 test doses asdescribed below and allowed a one week washout period between doses. Thetest doses included: (1) commercially available celecoxib in the form ofCELEBREX at 1 milligram per kilogram (mpk) combined with PEG 400:water(70:30) which was administered intravenously, (2) an oral dose ofcommercially available celecoxib in the form of CELEBREX at 5 mpkadjusted for each dog's weight in size 4 gelatin capsules, and (3) anoral dose of the sodium salt of the present invention as preparedaccording to Example 6 at 5 mpk adjusted for each dog's weight in size 4gelatin capsules. Details regarding formulations of the intravenous andoral doses can be found in FIG. 5A. Blood samples of approximately 2 mLin sodium heparin were obtained by jugular venipuncture at 0.25, 0.5, 1,3, 4, 6, 8, 12, and 24 hours post-dose. Additional samples were obtainedpredose and at 0.08 hr for the IV study. Blood samples were immediatelyplaced on ice and centrifuged within 30 minutes of collection. Plasmasamples (˜1.0 mL) were harvested and stored in 4 aliquots of 0.25 mL at−20 degrees C. Plasma samples were analyzed for celecoxib using anLC-MS/MS assay with a lower limit of quantitation of 5 ng/mL.Pharmacokinetic profiles of celecoxib in plasma were analyzed using thePHAST software Program (Version 2.3, Pheonix Life Sciences, Inc.). Theabsolute bioavailability (F) is reported for oral doses relative to theIV dose.

FIG. 5B shows the mean pharmacokinetic parameters (and standarddeviations thereof) of celecoxib in the plasma of male dogs following asingle oral or single intravenous dose of celecoxib or celecoxib sodiumsalt. The maximum blood serum concentration and bioavailability oforally-administered celecoxib sodium salt was about three- and two-foldgreater, respectively, than a roughly equal dose of orally-administeredcelecoxib, and the maximum blood serum concentration of celecoxib sodiumwas reached 40% faster than for celecoxib. FIG. 6 shows the dissolutionof celecoxib in the plasma of male dogs following a single oral orsingle intravenous dose of celecoxib or celecoxib sodium salt.

All novel combinations of form and formulation performed significantlybetter than the commercial product, Celebrex. The supporting data forthis conclusion are detailed in FIG. 5B and are summarized as follows:(1) The formulations were fully bioavailable versus only 40 percentbioavailable for Celebrex; (2) The formulations had pharmacokineticsthat were linear with dose, as shown in FIG. 5C, which was not the casewith Celebrex; and (3) A half dose of the formulations (i.e., 2.5 mg/kg)exhibited a mean celecoxib plasma level that was 5-fold greater that afull dose of Celebrex (5 mg/kg) in the first 15 minutes post dosing. Thelast observation, illustrated in FIG. 5B, indicates an improved rate oftherapeutic onset for the formulations of the present invention.

FIG. 5B shows mean pharmacokinetic parameters of celecoxib in plasmafollowing administration of IV and oral doses. Definitions of theparameters are as follows: (a) Cmax: peak concentration; observed value;(b) Tmax: Time to Cmax; observed value; (c) AUC(I): The area under theplasma concentration versus time curve from time zero to infinity; (d)t_(1/2): Terminal phase half-life; (e) F: Relative oral bioavailability;and (f) CL/F: Plasma clearance of the absorbed fraction. The number ofbeagles used per formulation are identified by the superscript next tothe formulation name, where (i) a refers to n=6; (ii) b refers to n=3;and (iii) c refers to n=2.

EXAMPLE 8

Celecoxib Lithium Salt Preparation Method: MO-116-49B

To celecoxib (101.4 mg; 0.2656 mmol) was added an aqueous solution ofLiOH (0.35 M; 1.05 mL; 0.37 mmol). The mixture was gently heated duringdissolution with occasional swirling until the solid dissolved. Thewater was evaporated with flowing nitrogen gas to yield a whitecrystalline solid. Characterization of the product mixture was achievedvia DSC (FIG. 14), TGA (FIG. 15), Raman spectroscopy (FIG. 16) and PXRD(FIG. 17) and showed the presence of celecoxib Li salt. Furtherpurification of the drug to remove the excess base can be achieved viarecrystallization.

Results of the DSC thermogram (FIG. 14) show an endotherm at 111.84degrees C. and a second endotherm at 237.11 degrees C. Results of theTGA (FIG. 15) demonstrated a 14% weight loss between about 25 degrees C.and 190 degrees C. Results of Raman spectroscopy show multiple spectralpeaks that can be used to characterize the salt. These include any one,any two, any three, any four, any five, any six, any seven, any eight,any nine, any ten, or any other combination of peaks of FIG. 16, e.g.,1617, 1597, 1450, 1374, 1115, 1063, 976, 801, 741 and 634 cm⁻¹. The PXRDpattern has characteristic peaks as shown in FIG. 17. PXRD peaks thatcan be used to characterize the salt include any one, or combination ofany two, any three, any four, any five, any six, any seven, any eight,any nine, any ten, any eleven, or any other combination of 2-thetaangles from FIG. 17, e.g., 4.14, 9.04, 10.705, 12.47, 15.08, 15.75,18.71, 19.64, 20.52, 21.55 and 23.00 degrees. A 0.8 mm collimator wasused during acquisition of the diffractogram.

EXAMPLE 9

Celecoxib Potassium Salt: Preparation Method MO-116-49A

To celecoxib (100.7 mg; 0.2637 mmol) was added an aqueous solution ofKOH (0.35 M; 1.15 ml; 0.40 mmol). The mixture was gently heated duringdissolution with occasional swirling until the solid dissolved. Thewater was subsequently evaporated with flowing nitrogen gas to yield awhite crystalline solid. Characterization of the resulting mixture wasperformed via DSC (FIG. 18,) TGA (FIG. 19), Raman spectroscopy (FIG. 20)and PXRD (FIG. 21) and verified the presence of celecoxib K salt.Further purification of the drug to remove the excess base could beachieved via recrystallization.

The results of the DSC analysis are depicted in the graph of FIG. 18 andshow that the mixture has an endotherm at 87.4 degrees C. The results ofthe TGA are depicted in FIG. 19 and show a 5.8 wt % loss between 25 and200 degrees C. A shoulder in the data is seen at 80 degrees C. The Ramanspectrum is depicted in FIG. 20 and show characteristic Raman shift(cm⁻¹) peaks at positions including, but not limited to any one orcombination of any two, any three, any four, or all five of the peaks:1618, 1448, 1374, 976, and 801 cm⁻¹, or any combinations of 1, 2, 3, 4,5, or more peaks of FIG. 20. The PXRD pattern has characteristic peaksas shown in FIG. 21. Peaks can be seen at 2-theta angles including, butnot limited to, 4.03, 9.11, 12.23, 15.35, 18.87, 19.79, 20.97, and 22.81degrees. The crystal can be characterized by any one or combination ofany two, any three, any four, any five, any six, any seven, or all eightof the above angles or any one or any number combination of 2-thetaangles of FIG. 21. A 0.8 mm collimator was used during acquisition ofthe diffractogram.

EXAMPLE 10

Celecoxib Potassium Salt: Preparation Method MO-116-55D

A suspension of celecoxib (100.2 mg; 0.2627 mmol) in toluene (2.2 mL)and methanol (0.1 mL) was gently warmed to yield a solution. To thesolution was added 3M aqueous KOH (0.090 ml; 0.027 mmol). After theresulting phase separation, the aqueous phase was removed and dried byflowing nitrogen gas. The resulting crystalline solid was characterizedvia TGA (FIG. 22), Raman spectroscopy (FIG. 23), and PXRD (FIG. 24).

The TGA sample was heated at 10 degrees C./min to 90 degrees C., heldfor 10 minutes, ramped 10 degrees C./min to 300 degrees C., and held for10 minutes with 40 mL/min nitrogen purge gas. The results are depictedin FIG. 22 and show a weight loss of about 4.9 wt % from 25 degrees C.to 200 degrees C. and 2.9 wt % at a shoulder from about 70 degrees C. to200 degrees C. This weight loss may indicate some level of solvation orresidual solvent. The Raman spectrum of the solid is depicted in FIG. 23and shows characteristic Raman shift (cm⁻¹) peaks at positionsincluding, but not limited to any one or a combination of any two, anythree, any four, any five, any six, any seven, any eight, any nine, anyten, or all eleven of the peaks 1616, 1446, 1374, 1233, 1197, 1109,1061, 973, 799, 740, or 633 cm⁻¹, or any one or combinations of 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more peaks of FIG. 23. The PXRDpattern is depicted in FIG. 24 and shows characteristic peaks at 2-thetaangles of 3.93, 10.83, 12.11, 15.07, 17.79, 18.57, 19.95, 24.77, and26.97 degrees. Any one, any two, any three, any four, any five, any six,any seven, any eight, any nine, or more of these peaks or those listedin FIG. 24 may be used to characterize celecoxib potassium salt.

EXAMPLE 11

Celecoxib Calcium Salt: Preparation Method MO-116-62A

To celecoxib (100 mg; 0.262 mmol) was added a solution of 1 M NaOH inmethanol (0.29 mL; 0.29 mmol). The mixture was gently warmed withoccasional swirling until all the solids were dissolved resulting in acolorless solution. To the solution was added a 3 M CaCl₂ solution inmethanol (0.131 mL; 0.393 mmol). A solid formed within minutes. Theprecipitate was filtered and the powder was dried overnight with flowingnitrogen gas. Characterization of the product mixture was achieved viaTGA (FIG. 25), Raman spectroscopy (FIG. 26), and PXRD (FIG. 27) andshowed the presence of celecoxib Ca salt and NaCl.

Results of the TGA (FIG. 25) show a total loss of 4.2 wt % between 25and 200 degrees C. The Raman spectrum shows characteristic Raman shift(cm⁻¹) peaks at positions including, but not limited to, any one, anytwo, any three, any four, any five, any six, or all seven of the peaks1617, 1598, 1450, 1377, 973, 801, 642, or any combinations of 2, 3, 4,5, 6, 7 or more peaks of FIG. 26. The PXRD pattern shows 2-theta anglesat 3.91, 7.82, 9.27, 11.66, 20.56, and 23.08 degrees. Any one or acombination of 2, 3, 4, 5, or more of the preceding peaks can be used tocharacterize the salt, as well as, any 1, 2, 3, 4, 5, 6, or more peaksof FIG. 27. The peaks at 27.35 and 31.67 degrees 2-theta are due toNaCl.

EXAMPLE 12

Comparative Analysis of Neutral Celecoxib

To aid in the analysis of some of the data retrieved, commerciallyavailable celecoxib was subjected to the same analytical techniques ofpowder X-ray diffraction (PXRD) and Raman spectroscopy. The results wereused as a comparison for the salts of the present invention.

Comparison Data: Celecoxib (PXRD)

A small amount of commercially available celecoxib was placed in a 0.3mm glass PXRD tube. The tube was placed in Rigaku D/Max Rapid PXRD setto Cu; 46 kV/40 mA; Collimator: 0.5 mm; Omega-axis oscillation, Pos(deg)0-5, speed 1; Phi-axis spin, Pos 360, Speed 2; Collection time was 15minutes. The results are depicted in FIG. 28.

Some of the peaks of the free acid may also be found in the compositionsof the present invention. As a further means of characterizing thecompositions of the present invention, the peaks characteristic of thefree acid, as shown in FIG. 28, may also be specifically excluded fromcompositions of the present invention.

Comparison Data: Celecoxib (Raman)

A small quantity of commercially available celecoxib was placed on aglass slide and mounted in the Thermo Nicolet Almega Dispersive Ramanspectrometer. The sample capture was set to 6 background scans and 12sample collection scans. The results are depicted in FIG. 29. Animportant feature in the Raman spectrum of celecoxib free acid is a peaknear 906 cm⁻¹. This peak is not found in the Raman spectra of thesodium, potassium, lithium, and calcium salts of the present invention.

EXAMPLE 13

Solid-State Formulations of Celecoxib Sodium Salt Hydrate

Solid-state formulations based on selected PLURONIC excipients incombination with hydroxypropylcellulose (HPC) and the crystallinecelecoxib sodium hydrate salt, prepared using traditional mortar andpestle technique, showed enhanced dissolution of the celecoxib salt insimulated gastric fluid.

This example demonstrates that related solid-state formulations enhancethe dissolution and retard the precipitation of celecoxib salts ascompared to the celecoxib neutral free acid compound. The processes usedto identify and test the preferred excipients in these examples aretwo-fold: (1) A “precipitation retardation assay” was used to identifyexcipients that supersaturate celecoxib in solution; and (2) In-vitrodissolution studies were performed on selected excipients to verify the“precipitation retardation assay” results.

EXAMPLE 14

Precipitation Retardation Assay

Precipitation Retardation Assay—Method

1. 58 excipients according to Table 2 were prepared at a concentrationof 1.8 mg/mL (0.18% by weight) in simulated gastric fluid (SGF) having200 mM hydrochloric acid and dispensed in quadruplicate in 96-wellplates at a volume of 150 microliters. SGF without excipients was usedas a negative control. The composition of SGF was 2 g/L sodium chloride,1 g/L Triton X-100, and 200 mM HCl in deionized water. TABLE 2Excipients used in Precipitation Retardation Assay Alkamus 719Polyethyleneglycol PLURONIC P123 Monooleate (Mapeg 400-MO) Alkamus EL620 Polyethyleneglycol PLURONIC P85 300 Alkamus EL 719 PLURONIC 17R2Poloxamer 188 Benzyl Alcohol PLURONIC F108 Poloxamer 338 Cremophor ELPLURONIC F127 Polypropyl 52 Cremophor RH40 PLURONIC F38 Polysorbate 40Crillet 1 HP PLURONIC F68 Polysorbate 80 Crovol A-70 PLURONIC F77Propylene Glycol Ethosperse G-26 PLURONIC F87 Polyvinylpyrrolidone 10KEthylene Glycol PLURONIC F88 Polyvinylpyrrolidone 360K Glycerin PLURONICF98 Polyvinylpyrrolidone 55K HEC 250K 2-Ethoxyethanol SaccharinHydroxypropylcellulose PLURONIC L31 Sodium lauryl sulphate (HPC)Isopropanolamine PLURONIC L43 Tagat 02 Myrj 52 PLURONIC L44 Transcutol PPolyethyleneglycol 1000 PLURONIC L92 Triacetin Polyethyleneglycol 200PLURONIC P103 Triethanol amine Polyethyleneglycol 400 PLURONIC P104Vitamin E TPGS Polyethyleneglycol 600 PLURONIC P105 Vitamin E TPGS & HPC

-   -   2. The 96-well plates were sealed, and incubated to a        temperature of 40 degrees C. for 20 minutes. After incubation,        the plate seals were removed.    -   3. Celecoxib, pre-dissolved in potassium hydroxide at 5.5 mg/mL,        was dispensed in 15 microliter aliquots to each well and        immediately mixed to give a final celecoxib concentration of 0.5        mg/mL per well. The final excipient concentration was 1.8 mg/mL.        The assay plate was sealed using an optically clear seal.    -   4. A nephelometer (Nephelostar Galaxy, BMG Technologies, Durham,        N.C.), with a chamber preheated to 37 degrees C., was used to        analyze the ability of the excipients to retard the        crystallization/precipitation of supersaturated celecoxib via        light scatter measurements.        Precipitation Retardation Assay—Results:

FIG. 30 shows precipitation retardation time for celecoxib as a fuictionof excipient in simulated gastric fluid (SGF). Final concentration ofcelecoxib was 0.5 mg/mL. Black bars indicate precipitation retardationtime that may be greater than 60 min. Excipients listed in Table 8, butexcluded from FIG. 30 did not show any appreciable precipitationretardation time (i.e., greater than 1.5 minutes). Nineteen of 58excipients were found to retard recrystallization/precipitation ofcelecoxib.

The presence of six PLURONIC (poloxamer) excipients among successfulprecipitation retardants prompted further study of these compounds.PLURONICs are ethylene oxide—propylene oxide block copolymers, whoseproperties can be significantly altered (e.g., melting point, cloudpoint, molecular weight, HLB number, critical micelle concentration,surface tension, interfacial tension, etc.) by adjusting the ratio ofcopolymer blocks. Further examination of these properties showed thatthe surface tension of these copolymers at a 0.1% concentration in watercorrelates with the ability to retard the crystallization/precipitationof celecoxib. PLURONIC excipients having low interfacial tension (i.e.,less than about 10 dyne/cm) or having a surface tension less then about42 dyne/cm were more effective at keeping celecoxib in solution thanPLURONIC excipients having high interfacial tension or surface tension.This observation is illustrated in FIG. 31A, along with interfacial datafor PLURONICs that were not tested.

FIG. 31A shows interfacial tension values of selected PLURONICexcipients in water. PLURONIC excipients having low interfacial tensioncorrelated with excipients that retarded crystallization/precipitationof celecoxib in simulated gastric fluid. An interfacial tensionthreshold for precipitation retardation was loosely defined as less thanabout 9 or 10 dyne/cm. The excipient concentration in the assay was0.18%; celecoxib concentration was 0.5 mg/mL. Interfacial data obtainedfrom BASF at 0.1% concentration in water versus mineral oil at 25degrees C. (PLURONIC is a trademark of BASF). It is important toemphasize that the Pluronics were used at a 1.8 mg/mL concentration inthis assay. It is suggested that a higher interfacial and surfacetension threshold will correlate with the ability to prevent celecoxibprecipitation when the Pluronics are used at a higher concentration.

The precipitation retardation data obtained using the Pluronicexcipients was further correlated to critical micelle concentration(CMC) values as a function of temperature. In this analysis, thedependence of CMC values as a function of propylene oxide content (i.e.,PPO units) at both 25 and 37 degrees is illustrated in FIG. 31B, wherethe concentration values of the Pluronic excipients used in the screenare overlayed for comparison. As shown in FIG. 31, effective retardantsat 37 degrees C. had a propylene oxide content greater than 40 PPObecause the retardants were used at a concentration higher than the CMCvalue. At 25 degrees C., the number of effective retardants becamesmaller because the use level of the Pluronic compounds fell below theCMC value at this temperature. A concentration of Pluronic excipientsgreater than the CMC is thus preferred for preventing immediateprecipitation of celecoxib. The reported CMC data was obtained from V.M. Nace, in Nonionic Surfactants (V. M. Nace, Ed.), Marcel Dekker, NewYork, 1996, pp 78-80.

EXAMPLE 15

In Vitro Dissolution Studies of PLURONIC Excipients

In Vitro Dissolution Studies of PLURONIC Excipients—Method

1. Celecoxib Preparation

-   -   a. Fresh celecoxib sodium salt hydrate was prepared and analyzed        to be approximately 90 percent free acid vs. sodium content.    -   b. The celecoxib salt was ground using mortar and pestle until        fine powder was formed. The fine powder was sieved using a 105        micrometer pore size mesh and stored in a 20 mL scintillation        vial at room temperature.

2. Formulation Preparation

-   -   a. Fresh PLURONIC excipient was dispensed into a mortar. If        initially a solid at room temperature, the PLURONIC was ground        until a smooth powder was formed.    -   b. If hydroxypropylcellulose (HPC) was to be added, it was        dispensed after the PLURONIC excipient. The HPC was combined        with the PLURONIC and the two were ground together using a        pestle and mixed with a spatula for 1 minute.    -   c. 105 micrometer sieved celecoxib salt was added to mortar and        the mixture was ground and mixed for several minutes.    -   d. If needed, a liquid excipient such as Poloxamer 124, PEG 200,        or PEG 400 was added to the mortar as a granulating fluid-like        liquid to form an intimate contact between drug and excipient.        The mixture was ground and mixed until a uniform consistency was        observed in the solid-state mixture.

3. Dissolution Assay

-   -   a. A water bath was set up at 37 degrees C.    -   b. Simulated gastric fluid in the fasted state (SGF) was        prepared at pH 1.7 and diluted by a factor of five with        deionized water. The final pH was approximately 2.4. The        simulated gastric fluid was diluted by a factor of five to        simulate the effect of drinking a glass of water with the        medication. The SGF was pre-heated to 37 degrees C.    -   c. The formulation was placed in a 20 mL scintillation vial.    -   d. A 10 mm×3 m stir bar was added.    -   e. Diluted SGF was added to the formulation. The volume added        was set to satisfy a 2 mg/mL dose of celecoxib free acid.    -   f. The vial was placed in the water bath and allowed to stir.    -   g. At each time point, 0.9 mL of solution was extracted and        filtered through a 0.2 micrometer polyvinylflouridine filter.        The first ⅔ of filtrate was discarded as waste and the last ⅓        was collected into an eppendorf tube. 0.1 mL of the collected        filtrate was immediately transferred to an autosampler vial and        diluted by a factor of ten with 0.9 mL of methanol. The        autosampler vials were crimp sealed and submitted for content        analysis using high performance liquid chromatography with        ultraviolet detection.        In Vitro Dissolution Studies of PLURONIC Excipients—Results:    -   1. Dissolution of two PLURONIC excipients that had low        interfacial tension: PLURONIC P123 and F127. PLURONIC P123 was a        paste at room temperature, and resulted in a sticky formulation        of celecoxib salt. PLURONIC F127 was a solid at room temperature        and formed a flowable powder solid-state mixture with the        celecoxib salt. The dissolution results for these mixtures at        equal weight concentrations of excipient to celecoxib free acid        content are shown in FIG. 32. (Weight ratios for the dissolution        studies were based on the molar mass of celecoxib free acid.)        PLURONIC P123 gave enhanced dissolution of celecoxib salt, while        PLURONIC F127 did not. The poor performance of PLURONIC F127 in        enhancing celecoxib dissolution was due to the slow dissolution        of the excipient. In contrast, PLURONIC P123 was intimately        bound with the celecoxib salt in a “sticky” waxy mass, which        delayed the dissolution of celecoxib. This allowed the excipient        to dissolve to a greater extent prior to the full dissolution of        the celecoxib salt form.    -   2. Dissolution of celecoxib sodium hydrate was performed in the        presence of HPC using PLURONIC P123, PLURONIC F127, and PLURONIC        F87. PLURONIC F87 has a high interfacial tension value. Equal        weight concentrations of PLURONIC and HPC to celecoxib free acid        content were used in the formulations. The PLURONIC P123        formulation was sticky due to the pasty nature of the excipient.        The PLURONIC F127 and F87 formulation were flowable since these        excipients are solids at room temperature. Dissolution data for        these formulations are shown in FIG. 33. The data showed that        addition of HPC in the PLURONIC P123 formulation produced a        widening of the dissolution profile. In the PLURONIC F127        formulation, HPC enhanced the initial dissolution component of        the profile (i.e. <10 minutes). In contrast, no dissolution        profile was observed in the PLURONIC F87 formulation. Since        PLURONIC F87 has a high interfacial tension (17.4 dyne/cm), the        resulting data supports the correlation of precipitation        retardants with interfacial tension. Since the PLURONIC P123        formulation (i.e., sticky) showed a dissolution profile that was        enhanced to a greater extent than the PLURONIC F127 formulation        (i.e., loose powder) in terms of time to        recrystallization/precipitation, it was hypothesized that the        addition of an excipient that physically binds the components of        the PLURONIC F127 formulation will result in further dissolution        enhancement.    -   3. Dissolution of celecoxib sodium,hydrate using PLURONIC F127        and HPC was performed using a granulated fluid-like liquid to        bind the solid-state mixture. Three granulating fluid-like        liquids were chosen: PEG 200, PEG 400, and Poloxamer 124. Equal        weight ratios of celecoxib free acid content, PLURONIC F127, and        HPC were formulated with 40-45% celecoxib free acid weight of        granulating fluid. The effect of these formulations on        dissolution is shown in FIG. 34. The granulating fluid-like        liquids increased the dissolution of celecoxib, possibly by        delaying the contact between the celecoxib salt and the        dissolution media until PLURONIC F127 had been dissolved to a        significant extent.        Dissolution of celecoxib sodium hydrate was then measured from a        compacted formulation containing PLURONIC F127 and HPC        excipients. Formulations containing equal weight ratios of        celecoxib free acid content, PLURONIC F127, and HPC were mixed        and compacted into 6 mm discs at 4900 psi. Dissolution results,        shown in FIG. 35A, indicated enhanced dissolution with onset        retarded by approximately 15-20 minutes. The compaction process        produced a similar effect on dissolution to that observed by the        addition of a granulating fluid (see FIG. 34) with the addition        of a delayed release mechanism. The delayed release        characteristic of the profile can be modulated by selecting HPC        or HPMC with varying grades of viscosity and the addition of        disintegrants into the compact. Compacts are attractive        formulations due to their lower production cost and fewer        processing steps. FIG. 31B shows the concentration of PLURONIC        excipients as a function of polypropylene oxide (PPO) units.        This figure shows that PLURONIC concentrations greater than the        CMC are preferred for effectively inhibiting precipitation.

The data collected thus far, assumped that both initial solubilizationand precipitation inhibition were needed to achieve enhanced dissolutionof celecoxib. To confirm this assumption, free acid celecoxib was testedin the selected precipitation inhibition excipients: Pluronic F127 andHPC. As shown in FIG. 35B, the dissolution of celecoxib did not show asupersaturation component. The small but measurable increaseddissolution over the commercial formulation (i.e., Celebrex) reflectsthe enhanced thermodynamic solubility of the celecoxib free form in theexcipient solution. These data highlight the importance of a novel formto serve as a “spring” and provide a good driving force forsupersaturation to occur. In the precipitation inhibition screen thedriving force was pre-solubilized celecoxib freeacid in 1 M potassiumhydroxide.

FIG. 35B shows the dose of celecoxib free acid in the dissolution mediumwas 2 mg/ml. The parachute component was comprised of a surfactant,Pluronic F127, and an enhancer, 100,000 MW hydroxypropylcellulose (HPC)at equal mass ratios of celecoxib free acid. “Springs” refer tocelecoxib free acid dissolved in either 2:1 PEG400:DI Water orTranscutol P. “No spring” refers to neat celecoxib free acid.DI=deionized, Transcutol P=diethylene glycol monoethyl ether.Dissolution was performed at 37 degrees C.

To test if the “parachute” concept (i.e., surfactant or surfactant plusenhancer) enhances the dissolution of these springs, we decided toco-formulate several species with Pluronic F127 and HPC. The dissolutiondata obtained with these “springs”, FIG. 35B, strongly suggest a“parachute” (surfactant or surfactant plus enhancer) is needed for anyappreciable dissolution. Addition of “parachutes”, such as of PluronicF127 and HPC, enabled the dissolution.

Dissolution was performed on a selection of celecoxib “springs” togeneralize the concept that the “parachutes” function independently of“spring” type. In these experiments, it was assumed that the selected“springs” were “strong enough” to drive the compound of interest intosolution. Once in solution, the “spring” component is theoreticallyexhausted and the “parachute” component takes an active role inretarding precipitation. The following celecoxib “springs” werecompared: (i) freeacid; (ii) sodium hydrate; (iii) sodium propyleneglycol solvate; (iv) n-methyl pyrolidone (NMP) solvate; and (v)celecoxib:nicotinamide co-crystal. The parachute(s) used in thecomparison was a combination surfactant and enhancer, Pluronic F127 andHPC, at same celecoxib free acid mass concentrations. A granulatingagent such as Pluronic LA4 or PEG400 was added to some of the samplesfor the purpose of determining its effect on the dissolution profile.The results shown in FIG. 35C confirm that the “parachute” maintainedsupersaturated levels of celecoxib when a spring was used. The free acidsample, which represents a spring with zero strength, showedconcentration levels that were below those concentrations obtained forthe other springs.

FIG. 35C shows spring enhanced celecoxib dissolution in presence ofparachute. The dose of celecoxib free acid in the dissolution media was2 mg/ml. The implied parachute in all samples was the combinedsurfactant and enhancer, Pluronic F127 and 100,000 MW HPC, at equal massratios of celecoxib free acid. PG=propylene glycol, NMP=n-methylpyrolidone, PEG400=polyethylene glycol with an average molecular weightof 400 Da. Dissolution was performed at 37 degrees C.

EXAMPLE 16

General Method of Precipitation Retardation Assay

The methods described above are specific examples of general methods ofthe present invention aimed at identifying excipients that retard thenucleation of solid-state API, their derivatives, and othernon-pharmaceutical compounds of marketable interest from a solutionsupersaturated with API. The method is outlined in FIG. 36 and isdescribed as follows:

-   -   1. Excipients are dissolved to a desired concentration in        de-ionized (DI) water or other media (i.e., simulated gastric or        intestinal fluids).    -   2. API is dissolved in a suitable solvent in which it has high        solubility (i.e., acidic pH environment for free base type API;        and basic pH environment for free acid type API).    -   3. The excipient solutions are dispensed into an assay plate        (i.e., 96-well or 384-well optically clear plate) either        manually or using automated liquid handling equipment. The        excipients can be added as single, binary, ternary, or higher        order excipient combinations into each well. An example of a        liquid handling instrument is the Tecan Genesis (Tecan U.S. Inc,        Research Triangle Park, N.C.).    -   4. The API solution is dispensed into the assay plate. The API        solution can be dispensed one well at a time, by rows, or        columns using the Tecan Genesis instrument or simultaneously        into all wells using the Tecan Genmate instrument. The volume of        API solution added is restricted to a small size to avoid        causing any shifts in the properties of the excipient solution.    -   5. The solutions are mixed to uniformly distribute the API        throughout the excipient solution. The plate is sealed and        incubated at a desired temperature.    -   6. Onset of solid-state nucleation is determined using an        instrument capable of measuring scattered light. Examples of        scattered light measurement capable instruments are the        NepheloStar nephelometer (BMG Technologies, Durham, N.C.) and        the SPECTRAmax PLUS plate reader (Molecular Devices Corp,        Sunnyvale, Calif.). Temperature is maintained at a constant        pre-defined set point by the incubation features of the        instruments.    -   7. Birefringence screening, PXRD, etc. may be performed to        determine if precipitated API is amorphous or crystalline. If        the API is crystalline, crystal habit and particle size can be        recorded.    -   8. The data are analyzed and the excipients are ranked according        to their respective retardation times.        Informatics may be used to correlate successful excipients that        retard nucleation with physical property information.

EXAMPLE 17

Illustration of Resulting Precipitation Retardation Data

Goal: Identify excipients that retard the solid-state nucleation ofCompound A in Fluid F at a temperature of 37 degrees C.

Method:

-   -   1. 24 excipient solutions were prepared at a concentration of 16        mg/mL in de-ionized water.    -   2. Fluid F was prepared in de-ionized H₂O by mixing ingredients        at twice the desired final concentration.    -   3. API solution was prepared at a concentration of 5.5 mg/mL in        Fluid C.    -   4. The Tecan Genesis instrument was used to dispense a        combination of 75 microliters Fluid F, 18.75 microliters        excipient solution, and 56.25 microliters de-ionized H₂O into        each well of a 96-well plate. The final concentration of        excipient in each well was 2 mg/mL in Fluid F. The total fluid        volume per well was 150 microliters. Four replicate wells were        used for each single excipient solution. An example of the        layout is shown in FIG. 37.    -   5. The plate was sealed using a transparent seal and incubated        at 40 degrees C. for 20 minutes.    -   6. The seal was removed and 15 microliters of API solution was        dispensed simultaneously into all 96-wells. The final        concentration of API in each well was 0.5 mg/mL. (Note: The time        dependence for solid-state nucleation began as soon as the API        solution was added.)    -   7. The well contents were mixed and sealed using the transparent        seal.    -   8. The plate was placed on the Nephelostar instrument to collect        light scatter data over a 1 hour time period. The Nephelostar        incubated the plate at 37 degrees C. as specified in the goal of        the assay.    -   9. At the end of the assay, the data were analyzed using        Microsoft Excel® and retardation times were calculated. An        example of collected light scatter data is shown in FIG. 38.        Onset of solid-state nucleation is defined as the time when the        light scatter signal increases above the baseline signal. The        threshold limit for the increase of the light scatter signal        used to define a precipitation/crystallization event is usually        set at three times the standard deviation of the baseline signal        to take into account background noise. The threshold can be set        however, to a different value depending on the sensitivity of        the assay and the desired limit of        precipitation/crystallization.    -   10. The retardation times (if any) for the excipient solutions        were ranked. FIG. 30 shows a graphical representation of the        ranking.        Non-limiting examples of alternatives to this general method        include:    -   1. Retardation time can be measured as a function of excipient        concentration.    -   2. Retardation time can be measured as a function of API salt or        co-crystal concentration.    -   3. API can be concentrated in a non-aqueous medium prior to        assay.    -   4. Temperature can be varied and controlled according to a        desired specification.

EXAMPLE 18

Propylene Glycol Solvate of Celecoxib Sodium Salt

A propylene glycol solvate of the sodium salt of celecoxib was prepared.To a solution of celecoxib (312 mg; 0.818 mmol) in diethyl ether (6 mL)was added propylene glycol (0.127 mL, 1.73 mmol). To the clear solutionwas added sodium ethoxide in ethanol (21%, 0.275 mL, 0.817 mmol). After1 minute, crystals began to form. After 5 minutes, the solid hadcompletely crystallized. The solid was collected by filtration and waswashed with additional diethyl ether (10 mL). The off-white solid wasthen air-dried and collected. The crystalline salt form was identifiedas a 1:1 solvate of propylene glycol. The solid was characterized by TGAand PXRD. The results are depicted in FIGS. 39 and 40A.

FIG. 39 shows the results of TGA. A weight loss of about 15.6% wasobserved between about 65 and 200 degrees C. which represents 1 molarequivalent of propylene glycol to celecoxib Na salt. FIG. 40A shows theresults of PXRD. Peaks, in 2-theta angles, that can be used tocharacterize the solvate include any 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ofthe following: 3.77, 7.57, 8.21, 11.33, 14.23, 16.13, 18.69, 20.65,22.69 and 24.77 degrees or any one or any combination of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, or more peaks of FIG. 40A. The TGA thermogram or PXRDdiffractogram data may be used alone or in any combination tocharacterize the solvate. A 0.8 mm collimator was used duringacquisition of the diffractogram.

Several closely related, yet distinguishable, PXRD diffractograms havebeen obtained by performing the above synthesis several times. FIGS.40B, 40C, and 40D are additional diffractograms of the propylene glycolsolvate of celecoxib sodium salt. A comparison of these diffractogramsyields a number of noticeable differences. For example, the peak at 8.21degrees 2-theta in FIG. 40A is not present in FIGS. 40B or 40C. Anotherpeak at 8.79 degrees 2-theta, present in FIGS. 40B and 40D, is not foundin FIGS. 40A or 40C. Other distinctions can also be found between thefour diffractograms. Such distinctions in otherwise similardiffractograms suggest the existence of polymorphism or perhaps avariable hydrate.

EXAMPLE 19

Propylene Glycol Solvate of Celecoxib Potassium Salt

A propylene glycol solvate of the potassium salt of celecoxib wasprepared. To a solution of celecoxib (253 mg, 0.664 mmol) in diethylether (6 mL) was added propylene glycol (0.075 mL, 1.02 mmol). To theclear solution was added potassium t-butoxide in tetrahydrofuran (THF)(1 M, 0.66 mL, 0.66 mmol). Crystals immediately began to form. After 5minutes, the solid had completely crystallized. The solid was collectedby filtration and was washed with additional diethyl ether (10 mL). Thewhite solid was then air-dried and collected. The crystalline salt formwas found to be a 1:1 propylene glycol solvate of celecoxib K salt. Thesolid was characterized by TGA and PXRD. The results are depicted inFIGS. 41 and 42.

FIG. 41 shows the results of TGA. A weight loss of about 14.94% wasobserved between about 65 and about 250 degrees C. which is consistentwith 1 molar equivalent of propylene glycol to celecoxib K. FIG. 42shows the results of PXRD. Peaks, in 2-theta angles, that can be used tocharacterize the solvate include any 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ofthe following: 3.75, 7.47, 11.33, 14.89, 15.65, 18.31, 20.49, 21.73,22.51, and 24.97 degrees or any one or any combination of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, or more peaks of FIG. 42.

EXAMPLE 20

Propylene Glycol Solvate of Celecoxib Lithium Salt

A propylene glycol solvate of the lithium salt of celecoxib wasprepared. To a solution of celecoxib (264 mg, 0.693 mmol) in diethylether Et₂O (8 mL) was added propylene glycol (0.075 mL, 1.02 mmol). Tothe clear solution was added t-butyl lithium in pentane (1.7 M, 0.40 mL,0.68 mmol). A brown solid formed immediately but dissolved within oneminute which subsequently yielded a white fluffy solid. The white solidcrystallized completely after 10 minutes. The solid was collected byfiltration and was washed with additional diethyl ether (10 mL). Thewhite solid was then air-dried and collected. The crystalline salt formwas found to be a 1:1 propylene glycol solvate of celecoxib Li. Thesolid was characterized by TGA and PXRD.

The results of TGA are depicted in FIG. 43 and show a weight loss ofabout 16.3% between 50 degrees C. and 210 degrees C. which is consistentwith 1 molar equivalent of propylene glycol to celecoxib Li. The resultsof PXRD are shown in FIG. 51. Characteristic peaks of 2-theta anglesthat can be used to characterize the salt include any one, orcombination of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of 3.79, 7.51,8.19, 9.83, 11.41, 15.93, 18.29, 19.19, 19.87, 20.63, 22.01, or 25.09degrees or any one or any combination of peaks of FIG. 51.

EXAMPLE 21

Propylene Glycol Solvate of Celecoxib Sodium Trihydrate

Preparation:

Celecoxib Na propylene glycol trihydrate was formed by allowing thecelecoxib sodium salt propylene glycol solvate to sit at 60% RH and 20degrees C. for 3 days. (Note: Formation of the trihydrate at 75% and 40degrees C. occurs as well). The trihydrate begins to form somewherebetween 31 and 40% RH at room temperature.

The solid was characterized by TGA and PXRD, which are shown in FIGS. 44and 45, respectively. FIG. 44 shows the results of the TGA where 9.64%weight loss was observed between room temperature and 60 degrees C. and13.6% weight loss was observed between 60 degrees C. and 175 degrees C.The PXRD pattern has characteristic peaks at 2-theta angles shown inFIG. 45. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks can be used tocharacterize the trihydrate, including for example, peaks at 3.47, 6.97,10.37, 13.97, 16.41, 19.45, 21.29, 22.69, 23.87, and 25.75 degrees.

The trihydrate can also be formed by crystallization of celecoxib Napropylene glycol solvate in the presence of H₂O. To a solution ofcelecoxib (136.2 mg; 0.357 mmol) in diethyl ether (6.0 mL), water (0.025mL; 1.39 mmol), and propylene glycol (0.030 mL; 0.408 mmol) was addedsodium ethoxide in ethanol (21 wt. %; 0.135 mL; 0.362 mmol). A solidformed within one minute and was isolated via filtration. The solid wasthen washed with additional diethyl ether (2.0 mL) and allowed to airdry. This procedure gives essentially the same PXRD pattern but there isa slight excess of water, which is probably surface water.

The solid was characterized by TGA and PXRD, which are shown in FIGS. 46and 47, respectively. FIG. 46 shows the results of TGA where 10.92%weight loss was observed between room temperature and 50 degrees C. and12.95% weight loss was observed between 50 degrees C. and 195 degrees C.The PXRD pattern has characteristic peaks at 2-theta angles shown inFIG. 47. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more peaks can beused to characterize the trihydrate, including for example, peaks at3.43, 6.95, 10.25, 13.95, 16.39, 17.39, 17.75, 18.21, 19.43, 21.21,22.61, and 25.71 degrees. A 0.8 mm collimator was used duringacquisition of the diffractogram.

EXAMPLE 22

Isopropyl Alcohol Solvate of Celecoxib Sodium Salt

To a solution of celecoxib (204.2 mg; 0.5354 mmol) in diethyl ether (6.0mL) was added isopropanol (0.070 mL). To the colorless solution wasadded a solution of sodium methoxide (0.5 M; 2.52 mL; 6.75 mmol) inmethanol followed by hexanes (3.0 mL). The volatiles were reduced underflowing nitrogen gas. A white solid formed and was collected viafiltration. After drying, the solid was found to be an isopropanolsolvate (1.5:1 isopropanol:celecoxib) via TGA and PXRD.

The results of DSC, TGA and PXRD analysis are shown in FIGS. 48-50. FIG.48 shows the results of DSC analysis where an endotherm was observed at67.69 degrees C. The results of TGA, as shown in FIG. 49, revealed aweight loss of about 18.23% from about room temperature to about 120degrees C. which represents a 1.5 molar equivalent of isopropanol tocelecoxib Na. The PXRD pattern has characteristic peaks at 2-thetaangles shown in FIG. 50. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,or more peaks can be used to characterize the solvate, including forexample, peaks at 3.43, 7.03, 10.13, 11.75, 14.11, 16.61, 17.61, 18.49,19.51, 20.97, 22.33, 22.81, and 25.93 degrees 2-theta.

EXAMPLE 23

1:1 Celecoxib:Nicotinamide Co-Crystals

Celecoxib (100 mg, 0.26 mmol) and nicotinamide (32.0 mg, 0.26 mmol) wereeach dissolved in acetone (2 mL). The two solutions were mixed and theresulting mixture was allowed to evaporate slowly overnight. Theprecipitated solid was collected and characterized. Detailedcharacterization of the co-crystal was performed using DSC, TGA andPXRD. The results of DSC showed two phase transitions at 117.2 and 118.8degrees C. and a sharp endotherm at 129.7 degrees C. The results of TGAshowed decomposition beginning at about 150 degrees C. The results ofPXRD are shown in FIG. 52. Characteristic peaks that can be used tocharacterize the co-crystal include any one, or any combination of any2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, of the peaks at 3.77,7.56, 9.63, 14.76, 16.01, 17.78, 18.68, 19.31, 20.435, 21.19, 22.10,23.80, 24.70, 25.295, and 26.73 degrees 2-theta, or any combination ofpeaks in FIG. 52.

EXAMPLE 24

Hydrates of Celecoxib Sodium Salt and Celecoxib Sodium Propylene GlycolSolvate

Celecoxib sodium is a variable hydrate. To analyze the affect ofhydration on crystal structure, celecoxib sodium salt and celecoxibsodium salt propylene glycol solvate were analyzed by PXRD under 17percent, 31 percent, 59 percent and 74 percent constant relativehumidity (RH) at room temperature. An analysis of celecoxib sodiumhydrate and celecoxib sodium propylene glycol solvate was performed byincubating the samples at the above relative humidity levels at roomtemperature for 48 hours. The following table lists PXRD 2-theta angle(degrees) peaks at the different relative humidities. TABLE 3 CelecoxibSodium Salt and Celecoxib Sodium Propylene Glycol Solvate PXRD DataCelecoxib Sodium Celecoxib Propylene Sodium Glycol 17% 31% 59% 74% 17%31% 59% 74% 3.51 3.51 3.49 3.59 3.79 3.82 3.47 3.47 3.99 3.95 3.95 4.617.65 7.61 6.97 6.97 8.87 8.91 4.61 5.35 8.75 8.69 10.29 10.29 9.51 10.715.35 8.91 11.45 11.44 11.91 11.85 10.75 11.59 7.83 9.51 12.19 12.1913.03 12.97 11.59 11.97 8.91 10.71 16.47 15.29 13.95 13.97 13.39 13.319.19 11.29 18.43 15.88 16.41 16.41 18.47 14.45 11.65 12.99 19.21 16.4317.39 17.39 19.09 18.49 12.21 13.85 20.91 17.19 17.79 17.79 20.17 19.0712.97 14.43 22.13 18.45 18.23 18.23 21.55 20.13 13.87 14.83 22.95 19.1719.45 19.45 21.91 20.47 14.79 16.07 20.84 20.59 20.63 31.67 21.53 16.0516.75 22.09 21.27 21.27 21.85 17.47 17.13 22.95 22.67 22.63 22.77 18.4317.97 23.99 23.91 23.91 31.69 18.89 18.39 25.47 24.37 24.35 19.57 18.7131.05 25.71 25.71 20.13 19.63 29.09 27.83 20.43 19.89 31.33 29.11 21.5720.43 31.83 31.31 22.41 21.55 32.79 31.87 24.53 22.39 33.55 32.83 25.3723.43 33.59 25.75 24.55 27.23 25.35 27.69 25.71 29.49 27.17 30.11 27.6931.70 28.19 35.23 29.49 37.95 29.99 32.29 37.87

The composition can be characterized by any one or combination of any 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, or more peaks listed in Table 3 or anyone or combination of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or morepeaks of any one of FIGS. 53-60. FIGS. 53-56 are PXRD diffractograms ofcelecoxib sodium hydrates at 17 percent, 31 percent, 59 percent, and 74percent RH, respectively. FIGS. 57-60 are PXRD diffractograms ofcelecoxib sodium propylene glycol hydrates at 17 percent, 31 percent, 59percent, and 74 percent RH, respectively.

PXRD analysis of celecoxib sodium hydrate shows that crystal packingchanges as water is absorbed. (See FIG. 69 and dynamic moisture sorptiondata in Example 30.) PXRD analysis of celecoxib sodium propylene glycolsolvate indicates the presence of two unique crystal forms when exposedto varying amounts of humidity. (See FIG. 70 and dynamic moisturesorption data in Example 30.) Form I is present at 31 percent RH andbelow, while Form II is present at 59 percent RH and above.

EXAMPLE 25

Various Hydrates of Celecoxib Sodium Salt

Multiple celecoxib sodium salt samples, all form M1, varying inhydration (believed to range from about 0.54 equivalents of H₂O perequivalent of celecoxib) were assayed by PXRD. The PXRD patterns werethen grouped based on shared peaks. Several groups were identified withfour shown in FIG. 61. Group D is consistent with a mixture of amorphousand crystalline celecoxib sodium. Table 4 lists PXRD peakscharacteristic in common to groups A, B, and C and peaks that arespecific to each group. TABLE 4 Celecoxib Sodium Salt Hydrate PXRD DataPeaks common to all Peaks for form Peaks for form Peaks for formVariants of form M1 M1_A M1_B M1_C 3.7 ± 0.3°  9.5 ± 0.2°  9.5 ± 0.2°12.1 ± 0.2° 8.9 ± 0.2° 11.3 ± 0.2° 11.4 ± 0.2° 14.7 ± 0.2° 10.7 ± 0.2° 17.2 ± 0.2° 13.3 ± 0.2°  20 ± 0.2° 14.4 ± 0.2° 21.8 ± 0.3° 

EXAMPLE 26

Hydrate of Celecoxib Potassium Salt

A celecoxib potassium salt hydrate was prepared. To a solution ofcelecoxib (233.4 mg; 0.6120 mmol) in a methanolic potassium hydroxidesolution (1.008 M; 0.606 0.611 mL;) was added wet methanol (methanol 1.0mL; water 0.100 mL). The solution was then reduced nearly to dryness(0.5 mL) via evaporation with flowing nitrogen gas. To the residualsolution was added diethyl ether (6.0 mL) and the mixture was stirred.Within one minute, crystals started forming and the solid was completelycrystallized within 10 minutes. The solid was then filtered and allowedto air dry. The solid was characterized via TGA and PXRD.

The results of TGA and PXRD are shown in FIGS. 63 and 64. FIG. 63 showsthe results of TGA where an 8.36% weight loss was observed between roomtemperature and 140 degrees C. The PXRD pattern has characteristic peaksat 2-theta angles shown in FIG. 64. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,or more peaks can be used to characterize the celecoxib potassiumhydrate, including for example, peaks at 3.69, 8.99, 10.65, 11.11,13.35, 20.05, 21.45, 22.39, 24.77, and 26.71 degrees 2-theta.

EXAMPLE 27

Preparation of Celecoxib Sodium Salt Using Sodium Chloride

To a solution of celecoxib (1.787 g; 4.686 mmol) in 1 M sodium hydroxide(5.0 mL; 5.0 mmol) was added a solution of 1 M sodium chloride (5 mL).The mixture was stirred and cooled to give slow crystallization ofcelecoxib sodium salt. The solid was collected via filtration and waswashed with additional 1 M sodium chloride (10 mL). The solid wasallowed to dry under flowing nitrogen gas.

The results of TGA and PXRD are shown in FIGS. 65 and 66. FIG. 65 showsthe results of TGA where an 8.98 percent weight loss was observedbetween room temperature and 140 degrees C. including a 4.06 percentweight loss between about 50 degrees C. and 140 degrees C. The PXRDpattern has characteristic peaks at 2-theta angles shown in FIG. 66. Any1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more peaks can be used tocharacterize the celecoxib sodium salt, including for example, peaks at3.65, 8.95, 9.61, 10.77, 11.43, 14.01, 17.19, 18.33, 19.47, 19.99,20.61, 21.71, 22.57, and 25.81 degrees 2-theta.

EXAMPLE 28

In Vitro Dissolution Study of Incubated Celecoxib Sodium Hydrate SaltFormulations

In-vitro dissolution was performed on celecoxib formulations pre andpost incubation at 40 degrees C. for 18 weeks. The composition of thetest formulations was: (i) celecoxib sodium hydrate salt,hydroxypropylcellulose (HPC), and poloxamer 407; (ii) celecoxib sodiumhydrate salt, hydroxypropylcellulose (HPC), poloxamer 407, and PEG 400;and (iii) celecoxib sodium propylene glycol solvate,hydroxypropylcellulose (HPC), and poloxamer 407. Dissolution wasperformed using 5 times diluted simulated gastric fluid (0.3 mM TritonX-100) at 37 degrees C. in 20 mL scintillation vials with a magneticstirrer.

As illustrated in FIG. 67, the dissolution profiles for formulations(ii) and (iii) post 40 degrees C. incubation displayed small losses inpeak dissolution magnitudes versus the fresh formulations. This loss,however, should not impact the in-vivo bioavailability and dose-responseproperties of celecoxib, as was observed in the dog pharmacokineticssection, where it was shown that in-vitro dissolution profiles ofvarying peak magnitude correlate with dog pharmacokinetic profiles(i.e., the in-vivo—in-vitro correlation). In contrast to the dissolutionbehavior of formulations (ii) and (iii), formulation (i) exhibitedimproved dissolution which may result from slight melting of PluronicF127 at 40° C. Melted Pluronic F127 may provide a benefit to dissolutionsimilar to that provided by Pluronic L44 and PEG400.

EXAMPLE 29

Controlled Release Formulation of Celecoxib Sodium Propylene GlycolSolvate

A membrane coated system was selected to achieve controlled release ofcelecoxib. The membrane, an erodible polymer with low waterpermeability, controlled the release of celecoxib through an erosionprocess. The membrane is used to facilitate erosion of the coating inwater without permitting the water to enter the interior of the pellet.The rate of celecoxib release was controlled by applying the polymer atincreasing membrane thicknesses to sub-populations of pellets within thefinal formulation dose. Pellets with a thin polymer coat releasecelecoxib more quickly than pellets that have a thicker polymer coat.Modulation of the coating thickness across many pellets results in adistribution of drug release profiles. Factors that affect the rate ofpolymer erosion include polymer type, plasticizer content, temperature,solvent, curing, and coat thickness. The formulation used in thisexample was comprised of celecoxib sodium propylene glycol solvate,Pluronic F127, and hydroxypropylcelluse (100,000 MW) at equal weightequivalents of celecoxib free acid. The formulation was supplementedwith magnesium stearate at a concentration of 0.05 weight percent to aidin the compression and ejection of pellets. This formulation comprised30.4 weight percent celecoxib free acid.

Pellets were compressed at 10.3 MPa into 2 mm diameter pellets ofcylindrical shape. The cylindrical pellets had an average height of 1 mmand average weight of 3.8 mg. Polymer coatings (e.g., cellulose acetatephthalate (CAP), polyvinyl acetate crotonic acid copolymer) were appliedusing a spray coater. The values of coating thicknesses ranged from 15to 70 micrometers

The application of the polymer coat was designed to delay the release ofcelecoxib and prevent its rapid conversion to the free acid form priorto absorption. To elucidate how the coating affects delayed release anddissolution during a transit through the stomach, an assay was developedthat employed both SGF and SIF. This assay was a two step process where,dissolution was performed in SGF in the first step, and the SGF mediumwas replaced with SIF medium to complete the dissolution assay in thesecond step. Two assumptions were made: (1) the typical transit time inthe stomach for small food particles is 30 minutes; and (2) solubilizedcelecoxib is quickly absorbed thus justifying complete exchange of SGFhaving solubilized celecoxib with SIF.

In vitro dissolution was tested in both simulated gastric and intestinalfluids in the fasted state. As a specific example, dissolution wasperformed in simulated gastric fluid on celecoxib sodium propyleneglycol pellets coated with cellulose acetate phthalate containing 10percent by weight triethyl citrate plasticizer (approximately 64 μmcoating thickness). After about 30 minutes, the dissolution media wastransferred to simulated intestinal fluid. The dissolution profileshowed no celecoxib release in the first 30 minutes which is consistentwith the behavior of enteric coatings in low pH solutions. Once in thesimulated intestinal fluid, the coating began to erode and celecoxibsodium was released. A maximum concentration of 0.64 mg/ml was obtainedafter about 90 minutes in the assay (See FIG. 68). This exampledemonstrates that controlled release can be achieved by applying varyingcoating thicknesses with discrete populations of pellets in a drugcapsule. The controlled release of celecoxib can be achieved through acombination of coated formulation pellets and/or a combination offormulation powder with coated formulation pellets.

EXAMPLE 30

Dynamic Moisture Sorption Analysis of Celecoxib Salts, Hydrates,Solvates, and Co-Crystals

Moisture sorption analysis was performed using the DVS-1 apparatus(Surface Measurement Systems, Monarch Beach, Calif.) with a Cahn D-200microbalance (Thermo Cahn, Madison, Wis.). Each sample was placed in aclean glass crucible and equilibrated in the apparatus at a specifiedrelative humidity (RH) level. Initial equilibration was performed in theDVS apparatus, unless otherwise specified. After initial equilibration,RH was varied and change in mass was recorded over time as an indicationof moisture sorption. RH was controlled by varying flow rates of dry andwater saturated nitrogen streams at 25 degrees C.; the total combinedflow rate of both streams was kept constant at 200 standard cubic metersper minute. A full humidity cycle typically refers to a ramp from 0 to95 percent RH and back down 0 percent RH, unless otherwise specified.Mass equilibration at each humidity level was obtained when the changein mass per time value (i.e., dm/dt) was less than 2 micrograms/min.After the assay, change in mass, due to water sorption, wasmathematically converted to water molar equivalents per dry compoundmolar equivalent. Form analysis was performed at the end of the assay onselect samples using powder x-ray diffraction pattern (PXRD; D/MaxRapid, Rigaku, Danvers, Mass.). Samples were packed into 3 mm diameterborosilicate capillary tubes for the analysis.

Celecoxib Sodium Hydrate

Celecoxib sodium hydrate (dry mass: 9.2593 mg, dry molecular weight:404.36, temperature: 25.4 degrees C.) was initially equilibrated at 20percent RH at 25 degrees C. RH was ramped up from 20 percent to 95percent RH, and then ramped down to 0 percent RH. Two complete humiditycycles were performed as illustrated in FIG. 71. The moisture sorptionisotherms for both cycles overlapped indicating a lack of irreversibleform changes. In the transition from 0 to 10 percent RH the compoundadsorbed 1 water molar equivalent per dry compound. Water sorptionincreased steadily from 20 to 40 percent RH until approximately 3 waterequivalents were obtained at 40 percent RH. The trihydrate waskinetically stable in the 40 to 70 percent RH range. At RH valuesgreater than 70%, water sorption continued to rise until deliquescenceoccurred at 95 percent RH. Key observations in this assay were theformation of forms consistent with a tri-hydrate designation in the 40to 70 percent RH range and a monohydrate designation in the 10 to 20percent RH range.

Celecoxib Potassium

Celecoxib potassium (dry mass: 15.8563 mg, dry molecular weight: 419.48,temperature: 25.5 degrees C.) was initially equilibrated at 0 percent RHat 25 degrees C. RH was then ramped from 0 to 95 percent RH in a twocycle experiment, as illustrated in FIG. 72A. Water sorption wasstrongly dependent on RH with immediate adsorption occurring at very lowRH levels, and deliquescence occurring at 95 percent RH. The analysiswas characterized by very low hysteresis and large amounts of wateruptake. A PXRD pattern taken at the end of the assay, FIG. 72B, showedthe compound to be in the crystalline state. Small changes in form areapparent, as compared to the pre-incubation PXRD, indicating somecrystal rearrangement (i.e., polymorphism) associated with moisturesorption. The pre-incubation PXRD is representative of celecoxibpotassium that had been equilibrated at room temperature and ambienthumidity.

Celecoxib Sodium Propylene Glycol Solvate

Celecoxib sodium propylene glycol solvate (dry mass: 19.4851 mg, drymolecular weight: 480.45, temperature: 25.8 degrees C.) was initiallyequilibrated at 0 percent RH at 25 degrees C. RH was ramped from 0 to 75percent RH in a three cycle experiment as illustrated in FIG. 73. Nochange in mass was observed from 0 to 34 percent RH, indicating thepresence of a stable anhydrous form over this range. At 40 percent RH,the compound gained one water molar equivalent and monotonically keepsincreasing in water content up to 75 percent RH.

The desorption cycle was characterized by significant hysteresis whichis consistent with hydration processes. During water desorption waterwas shed very slowly until a dihydrate was formed below 40 percent RH.The dihydrate was stable from 33 to 17 percent RH. Upon further dryingto 0 percent RH, the sample continued to lose water before equilibratingat a weight lower than the original dry weight (i.e., 0 percent RH inCycle 1 Sorp). The additional loss of mass suggests propylene glycol wasreleased during the RH transitions. Assuming that the compound was dry(i.e., without water) at 0 percent RH, the calculated propylene glycolloss was 0.16 equivalents. Two additional humidity cycles were run toverify these observations. The additional cycles showed similar trendsto the first cycle, but on a lower y-axis scale due to the propyleneglycol mass loss. Furthermore, additional mass loss was observed at theend of each cycle. The total calculated propylene glycol loss at the endof the second and third cycles was 0.25 and 0.32 mass equivalents ofpropylene glycol respectively.

A second dynamic moisture sorption analysis was completed with celecoxibsodium propylene glycol solvate. In this trial, the sample was incubatedat 55 percent RH at room temperature for 72 hours in a salt bathsolution. In the moisture sorption analysis, the sample was removed fromthe 55 percent RH chamber and equilibrated at 20 percent RH at 25degrees C. in the dynamic moisture sorption instrument. RH was thenramped from 20 to 60 percent RH and down to 0 percent RH in the firstcycle. As shown in FIG. 74, a stable trihydrate was observed from 10 to60 percent RH. At 0 percent RH, the water molecules were shed to yieldan anhydrous form.

In the second humidity cycle, water began to adsorb at RH values greaterthan 20 percent. At 40 percent RH, 2 water equivalents had been absorbedwhich is consistent with a dihydrate form designation. This dihydratewas stable from 40 to 60 percent RH. At greater RH, water contentexponentially increased and deliquescence was observed at 95 percent RH.The desorption cycle was characterized by significant hysteresis below70 percent RH. Between 30 and 10 percent RH the dihydrate form wasreestablished. Upon further drying to 0 percent RH the sampleequilibrated at a weight lower the than original dry weight of thecompound. Assuming that the sample was completely dry, the calculatedpropylene glycol loss was estimated to be 0.16 molar equivalents.

A third humidity assay was begun, but was stopped shortly thereafter at30 percent RH prior to equilibration. As shown in FIG. 75, a PXRDpattern taken at this time showed form conversion, with respect to thestarting material, suggesting that water sorption involves rearrangementof the crystal structure.

The primary difference observed in this study, with respect to the firstcelecoxib sodium propylene glycol solvate analysis, was the presence ofa stable trihydrate form in 10 to 60 percent RH region followingequilibration at 55 percent RH for 72 hours. Because the observationsmade in the second humidity cycle were remarkably consistent with thosemade in the prior assay, assay reproducibility was confirmed. Thesefindings suggests that the dihydrate form was kinetically stable forextended time periods of time (i.e., hours) before converting to athermodynamically stable trihydrate form.

Celecoxib Potassium Propylene Glycol Solvate

Celecoxib potassium propylene glycol solvate (dry mass: 17.2584 mg, drymolecular weight: 496.57, temperature 25.1 degrees C.) was initiallyequilibrated in 0 percent RH at 25 degrees C. RH was ramped from 0 to 95percent RH in a one cycle experiment as illustrated in FIG. 76. Nochange in mass was observed from 0 to 43 percent RH, indicating thepresence of a stable anhydrous form over this range. Above 43 percentRH, water sorption increased exponentially with increasing percent RHuntil. Deliquescence was observed at 95 percent RH.

The desorption cycle was characterized by negative hysteresis consistentwith that observed for the sodium propylene glycol solvate form. At 30percent RH the sample equilibrated at a mass below that of the initialdry mass of the sample. This mass loss, attributed to removal ofpropylene glycol, was calculated to be 0.27 equivalents at 0 percent RH.A PXRD pattern (see FIG. 77) taken at the end of the assay showed thesample had converted to an amorphous form.

Celecoxib Lithium Propylene Glycol Solvate

Celecoxib lithium propylene glycol solvate (dry mass: 5.5916 mg, drymolecular weight: 387.32, temperature: 25.5 degrees C.) was initiallyequilibrated at 20 percent RH at 25 degrees C. RH was ramped up from 20to 95 percent RH and back down to 0 percent RH. Two complete humiditycycles were performed as illustrated in FIG. 78. In the initial 20 to 50percent RH transition the data shows 1 molar water equivalent wasdesorbed, assuming PG was not lost at this stage. Above 60 percent RHwater sorption increased exponentially with increasing percent RH beforedeliquescence occurred at 95 percent RH.

In the desorption cycles, a lower dry weight was consistently obtainedafter equilibration in 0% RH. The decreasing dry weight obtained at 0percent RH was consistent with the properties of other propylene glycolforms and suggests loss of propylene glycol during the RH ramp cycles.The calculated propylene glycol loss was 0.11 molar equivalents. A PXRDpattern, FIG. 79, taken at the end of the assay showed a change incrystalline form during the assay.

Celecoxib:Nicotinamide Co-Crystal

Celecoxib:Nicotinamide co-crystal (dry mass: 3.129 mg, dry molecularweight: 1044.8, temperature: 25.3 degrees C.) was initially equilibratedat 0 percent RH at 25 degrees C. RH was ramped from 0 to 95 percent RHin a two cycle experiment, as illustrated in FIG. 80. The co-crystal wasnot hygroscopic below 70 percent RH. The small amount of water contentobserved in the figure is attributed to surface adsorption. Above 70percent RH, water content increased gradually and reached a peakconcentration of 2 water molecules per mole of co-crystal at 95 percentRH. The desorption cycle was characterized by minimal hysteresis.

EXAMPLE 31

Amorphous Celecoxib Potassium Salt: Preparation Method MO-116-55B

To celecoxib (105.3 mg; 0.2761 mmol) was added aqueous 3M KOH (0.090 ml;0.27 mmol) to give a suspension. The suspension was gently warmed and toit was added methanol (0.3 mL) which yielded a colorless solution. Thesolution was cooled to room temperature and the volatiles weresubsequently evaporated with flowing nitrogen gas. The resultingamorphous solid was characterized via DSC, Raman spectroscopy, and PXRD.

The DSC is depicted in FIG. 81. The Raman spectrum is depicted in FIG.82 and shows characteristic Raman shift peaks (cm⁻¹) at positionsincluding, but not limited to any one or a combination of any two, anythree, any four, any five, any six, any seven, any eight, any nine, anyten, or all eleven of the peaks 1616, 1450, 1376, 1236, 1198, 1112,1063, 976, 800, 742, or 634 cm⁻¹, or any one or combinations of 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more peaks of FIG. 82. The PXRDpattern is depicted in FIG. 83 for which one peak is observed at 3.87degrees 2-theta.

EXAMPLE 32

Crystallization of Celecoxib and Valdecoxib with Various Ethers

Celecoxib: 18-crown-6 Co-Crystal

To solid 18-crown-6 (118.1 mg; 0.447 mmol) was added a solution ofcelecoxib (157.8 mg; 0.4138 mmol) in diethyl ether (10.0 mL). The opaquesolid dissolved immediately and a white solid subsequently began tocrystallize very rapidly. The solid was collected via filtration and waswashed with additional diethyl ether (5 mL).

The solid was allowed to air dry and was characterized via TGA, DSC, andPXRD. Unit cell determination by single crystal X-Ray diffraction isconsistent with a 2:1 adduct (celecoxib: 18-crown-6). The co-crystal hasa higher melting point (189 degrees C.) than celecoxib (156-159 degreesC.).

FIG. 84 shows the TGA thermogram of the celecoxib: 18-crown-6co-crystal. Results of the TGA analysis show an approximate 25 percentweight loss between about 125 degrees C. and 220 degrees C. FIG. 85shows the DSC thermogram of the celecoxib: 18-crown-6 co-crystal.Results of the DSC analysis shows an endotherm at 189.6 degrees C. FIG.86 shows the PXRD diffractogram of the celecoxib:18-crown-6 co-crystal.Peaks can be seen at 2-theta angles including, but not limited to, 8.73,11.89, 13.13, 16.37, 17.75, 18.45, 20.75, 22.37, and 23.11 degrees. Thecrystal can be characterized by any one or combination of any two, anythree, any four, any five, any six, any seven, any eight, or all nine ofthe above angles or any one or any combination of 2-theta angles of FIG.86.

Celecoxib 15-Crown-5 Solvate

To a solution of celecoxib (165.2 mg; 0.4332 mmol) in diethyl ether (5.0mL) was added a solution of 15-crown-5 (0.095 mL; 0.48 mmol) in diethylether (1.0 mL). The volatiles were allowed to evaporate slowly yieldingan oil. The oil was then recrystallized from ethanol (5 mL). Therecrystallization also yielded an oil that crystallized after 1 weekwithout agitation. The solid was found to be a 15-crown-5 solvate ofcelecoxib.

The solid was characterized via TGA, DSC, and PXRD. The TGA data shows aloss of 34.67 weight percent which is consistent with 1 molar equivalentof 15-crown-5 per mole of celecoxib (See FIG. 87). DSC shows a meltingpoint at 91.2 degrees C. which is significantly lower than that of the18-crown-6 analogue (189 degrees C.) and free celecoxib (156-159 degreesC.). The DSC thermogram is shown in FIG. 88. FIG. 89 shows the PXRDdiffractogram of the celecoxib 15-crown-5 solvate. Peaks can be seen at2-theta angles including, but not limited to, 7.67, 13.57, 14.61, 20.61,21.69, 23.07, and 24.81 degrees. The crystal can be characterized by anyone or a combination of any two, any three, any four, any five, any six,or all seven of the above angles or any one or any combination of2-theta angles of FIG. 89.

Celecoxib Diglyme Solvate

To a solution of celecoxib (129.3 mg; 0.3390 mmol) in diethyl ether (5.0mL) was added a solution of diglyme (0.100 mL; 0.698 mmol) in diethylether (3.0 mL). The volatiles were allowed to evaporate slowly yieldinga white solid. The solid continued to crystallize as the solvent wasreduced (2 mL) and subsequently cooled. The white powder was collectedvia filtration and air-dried. The solid was found to be a diglymesolvate of celecoxib.

The solid was characterized via TGA, DSC, and PXRD. The TGA data shows aloss of 24.85 weight percent which is consistent with 1 molar equivalentof diglyme per mole of celecoxib (See FIG. 90). The melting point of thesolvate is shown to be 98.2 degrees C. by DSC, which is significantlylower than celecoxib (156-159 degrees C.).). The DSC thermogram is shownin FIG. 91. FIG. 92 shows the PXRD diffractogram of the celecoxibdiglyme solvate. Peaks can be seen at 2-theta angles including, but notlimited to, 6.71, 10.77, 16.15, 20.53, 21.05, 21.81, and 22.69 degrees.The crystal can be characterized by any one or a combination of any two,any three, any four, any five, any six, or all seven of the above anglesor any one or any combination of 2-theta angles of FIG. 92.

Valdecoxib: 18-Crown-6 Co-Crystal

To a solution of valdecoxib (33.3 mg; 0.107 mmol) in tetrahydrofuran(2.0 mL) is added a solution of 18-Crown-6 (30.2 mg; 0.114 mmol) intetrahydrofuran (2.0 mL). The solution was stirred and was allowed toslowly evaporate. After evaporation to dryness, the residual solid was awhite crystalline material. A single crystal was removed for singlecrystal X-ray diffraction and was found to be a 2:1 adduct with twoindependent supramolecular complexes in the asymmetric unit. TGAanalysis of the valdecoxib: 18-crown-6 co-crystal is shown in FIG. 93.FIG. 94 shows the PXRD diffractogram of the valdecoxib: 18-crown-6co-crystal. Peaks can be seen at 2-theta angles including, but notlimited to, 11.31, 13.23, 16.01, 17.69, 18.19, 21.11, 21.59, 22.51,23.23, and 24.03 degrees. The crystal can be characterized by any one ora combination of any two, any three, any four, any five, any six, anyseven, any eight, any nine, or all ten of the above angles or any one orany combination of 2-theta angles of FIG. 94. FIG. 95 shows the singlecrystal structure of the valdecoxib: 18-crown-6 co-crystal.

Single-crystal x-ray data for the valdecoxib:18-crown-6 co-crystal 2:1are as follows:

-   -   Empirical formula C44 H52 N4 O12 S2    -   Formula weight 893.02    -   Temperature 100(2) K    -   Wavelength 0.71073 angstroms    -   Unit cell dimensions a=10.1721(11) angstroms alpha=83.127(2)        deg.        -   b=13.7178(15) angstroms beta=73.362(2) deg.        -   c=16.7202(18) angstroms gamma=89.017(2) deg.    -   Volume 2219.0(4)A³    -   Z, Calculated density 2, 1.337 Mg/m³    -   Absorption coefficient 0.187 mm⁻¹    -   F(000) 944    -   Reflections collected/unique 13432/9849 [R(int) =0.0330]    -   Refinement method Full-matrix least-squares on F²    -   Data/restraints/parameters 9849/0/559    -   Goodness-of-fit on F² 0.995    -   Final R indices [I>2sigma(I)] R1=0.0594, wR2=0.1345    -   R indices (all data) R1=0.1097, wR2=0.1573

The above co-crystals and solvates exemplify the importance of theether-sulfonamide interaction. This ether-sulfonamide interaction ishighly favorable and plays an important role in the formulations of thepresent invention.

EXAMPLE 33

Celecoxib NMP Solvate

To solid celecoxib (127 mg; 0.333 mmol) was added N-methyl-2-pyrrolidone(0.75 mL) to give a white suspension. The mixture was heated to 75degrees C. and held at this temperature for 3 minutes at which point thesolid dissolved to give a colorless solution. The solution was cooled toroom temperature and then cooled to 5 degrees C. for three days. Afterthree days, colorless hexagonal crystals had formed. The mother liquorwas decanted and the solid was suspended in pentane (2 mL) and filtered.The solid was air dried and collected. The solid was found to be a 1:1N-methyl-2-pyrrolidone (NMP) solvate of celecoxib.

The solid was characterized by TGA, Raman spectroscopy, and PXRD. TGAdata show an initial loss of 7.40% weight loss between room temperatureand 60 degrees C. which is attributed to residual solvent (See FIG. 96).Between about 95 degrees C. and about 165 degrees C., the solvate loses19.39 percent weight. This loss represents 1:1 molar equivalent of NMPto celecoxib. The residual solvent can be removed to give the puresolvate. Raman scattering peaks were found at, for example, 1615, 1451,1375, 1159, 973, 799, 741, and 626 cm⁻¹. Any one, any two, any three,any four, any five, any six, any seven, or all eight of the above or anyone or a combination of peaks in FIG. 97 can be used to characterize thecrystal. FIG. 98 shows the PXRD diffractogram of the celecoxib:NMPsolvate. Peaks can be seen at 2-theta angles including, but not limitedto, 8.19, 12.69, 15.01, 15.65, 16.37, 17.89, 19.37, 21.05 and 23.01degrees. The crystal can be characterized by any one or a combination ofany two, any three, any four, any five, any six, any seven, any eight,or all nine of the above angles or any one or any combination of 2-thetaangles of FIG. 98.

Single-crystal x-ray data for the celecoxib:NMP co-crystal at 100 K isas follows: Empirical formula C22 H23 F3 N4 O3 S Formula weight 480.50Temperature 100(2) K Wavelength 0.71073 angstroms Crystal systemMonoclinic Space group P2(1)/n Unit cell dimensions a = 21.1232(14)angstroms alpha = 90°. b = 9.2669(6) angstroms beta = 102.5320(10)°. c =23.8250(16) angstroms gamma = 90°. Volume 4552.5(5) Å³ Z 8 Density(calculated) 1.402 Mg/m³ Absorption coefficient 0.199 mm⁻¹ F(000) 2000Crystal size 0.20 × 0.15 × 0.10 mm³ Theta range for data collection 1.17to 28.33°. Index ranges −26 <= h <= 28, −11 <= k <= 12, −31 <= 1 <= 25Reflections collected 27520 Independent reflections 10573 [R(int) =0.0366] Completeness to theta = 28.33° 93.0% Absorption correction NoneRefinement method Full-matrix least-squares on F²Data/restraints/parameters 10573/0/729 Goodness-of-fit on F² 1.026 FinalR indices [I > 2sigma(I)] R1 = 0.0580, wR2 = 0.1386 R indices (all data)R1 = 0.0873, wR2 = 0.1547 Largest diff. peak and hole 0.694 and −0.655e.Å⁻³

FIG. 99 shows a packing diagram for the celecoxib:NMP solvate at 100 K.Single-crystal x-ray data for the celecoxib:NMP co-crystal at 571 K isas follows: Empirical formula C22 H23 F3 N4 O3 S Formula weight 480.50Temperature 571(2) K Wavelength 0.71073 angstroms Crystal systemMonoclinic Space group P2(1)/c Unit cell dimensions a = 12.0017(10)angstroms alpha = 90°. b = 9.0910(7) angstroms beta = 101.338(2)°. c =21.9595(18) angstroms gamma = 90°. Volume 2349.2(3) Å³ Z 4 Density(calculated) 1.359 Mg/m³ Absorption coefficient 0.192 mm⁻¹ F(000) 1000Crystal size 0.20 × 0.15 × 0.15 mm³ Theta range for data collection 1.73to 28.33°. Index ranges −14 <= h <= 15, −12 <= k <= 11, −29 <= 1 <= 24Reflections collected 14668 Independent reflections 5509 [R(int) =0.0226] Completeness to theta = 28.33° 94.2% Absorption correction NoneRefinement method Full-matrix least-squares on F²Data/restraints/parameters 5509/0/328 Goodness-of-fit on F² 1.041 FinalR indices [I > 2sigma(I)] R1 = 0.0597, wR2 = 0.1698 R indices (all data)R1 = 0.0950, wR2 = 0.1958 Largest diff. peak and hole 0.455 and −0.217e.Å⁻³FIG. 100 shows a packing diagram for the celecoxib:NMP solvate at 571 K.

EXAMPLE 34

Dissolution of Celecoxib Sodium Formulations with PotentialPrecipitation Inhibitors

The dissolution profile in SGF of solid mixtures of celecoxib sodiumwith excipients was studied at room temperature. Those mixtures thatprovided concentrations greater than 0.10 mg/mL at any time pointstudied are included in FIG. 10.

Poloxamer 237, vitamin E TPGS (TPGS), and Gelucire 50/13 were alleffective at providing elevated concentrations for some period of time.PVP and poloxamer 188 were less effective, but maintained measurableconcentrations for at least some period. The TPGS solutions appearedmostly clear, and were clear after filtration. The Poloxamer 237 samplesappeared milky, even after filtration.

Since the mixtures with poloxamer 237 and 188 led to widely differentsolubility profiles, other poloxamers were studied as well, and therelationship between poloxamer structure and dissolution profile wasevaluated (see FIG. 7). The weight ratio of drug to poloxamer is 1:1 forall profiles shown on the plot. Poloxamers 237 and 407 have a clearenhancement effect relative to poloxamers 188 and 338.

Poloxamers are block copolymers of polyethyleneglycol (PEG) andpolypropyleneglycol (PPG). FIG. 7 also shows the block composition foreach poloxamer studied. The solubility is enhanced by poloxamerscontaining a high composition of the PPG block.

FIG. 8 shows the effects of celluloses on dissolution of 1:1TPGS:celecoxib sodium at room temperature. The effect of excipientloading and ratio on the dissolution profile was tested and found tohave a profound impact on the dissolution profile (see FIG. 9). FIG. 10shows a dissolution profile of celecoxib sodium in SGF from solidmixtures with excipients at room temperature. FIG. 11 shows the effectof Avicel and silica gel on the dissolution of celecoxib sodium, TPGS,HPC formulations in SGF at 37 degrees C. FIG. 12 shows the dissolutionof celecoxib sodium salt in several formulations at 37 degrees C. in 5times diluted SGF.

It is noted that as used in the Figures, the terms “TPI336” and“TPI-336” refer to celecoxib or a salt of celecoxib depending upon thecontext.

1-45. (canceled)
 46. A pharmaceutical composition comprising: (a) a saltform of an API having an aqueous solubility less than about 10 mg/mL ingastric fluid conditions; (b) a precipitation retardant; and (c) anoptional enhancer; wherein the composition retards crystallization orprecipitation of the API for at least 5 minutes in gastric fluidconditions.
 47. The pharmaceutical composition according to claim 46,wherein the precipitation retardant is a surfactant.
 48. Thepharmaceutical composition according to claim 46, wherein theprecipitation retardant is a surfactant and exhibits an interfacialtension of less than about 10 dyne/cm or a surface tension of less thanabout 42 dyne/cm.
 49. The pharmaceutical composition according to claim46, wherein the precipitation retardant is a poloxamer.
 50. Thepharmaceutical composition according to claim 46, wherein thecomposition comprises an enhancer.
 51. The pharmaceutical compositionaccording to claim 46, wherein the composition comprises HPC or HPMC asan enhancer.
 52. The pharmaceutical composition according to claim 46,wherein crystallization or precipitation is retarded for at least 20minutes.
 53. The pharmaceutical composition according to claim 46,wherein crystallization or precipitation is retarded for at least 40minutes.
 54. The pharmaceutical composition according to claim 46,wherein crystallization or precipitation is retarded for at least 60minutes.
 55. The pharmaceutical composition according to claim 46,wherein the API is a sulfonamide.
 56. The pharmaceutical compositionaccording to claim 46, wherein the API is a benzene sulfonamide.
 57. Thepharmaceutical composition according to claim 46, wherein the API iscelecoxib, deracoxib, valdecoxib, rofecoxib or eturicoxib.
 58. Thepharmaceutical composition according to claim 46, wherein the salt formof the API is an alkali metal or alkaline earth metal salt.
 59. Thepharmaceutical composition according to claim 46, wherein the salt formof the API is a sodium, potassium, lithium, or calcium salt.
 60. Thepharmaceutical composition according to claim 46, wherein thebioavailability of the composition orally administered is at least 70%.61. The pharmaceutical composition according to claim 46, wherein thebioavailability of the composition orally administered is as least 80%.62. The pharmaceutical composition according to claim 46, wherein thebioavailability of the composition orally administered is as least 90%.63. The pharmaceutical composition according to claim 46, wherein theC_(max) is at least 2 fold greater than a neutral form in vivo or in anin vitro dissolution assay.
 64. The pharmaceutical composition accordingto claim 46, wherein the C_(max) is at least 4 fold greater than aneutral form in vivo or in an in vitro dissolution assay.
 65. Thepharmaceutical composition according to claim 46, wherein the C_(max) isat least 10 fold greater than a neutral form in vivo or in an in vitrodissolution assay.
 66. The pharmaceutical composition according to claim46, wherein the bioavailability of the composition is at least 50%greater than a neutral form.
 67. The pharmaceutical compositionaccording to claim 46, wherein the bioavailability of the composition isat least 2 fold that of a neutral form.
 68. The pharmaceuticalcomposition according to claim 46, wherein the bioavailability of thecomposition is at least 5 fold that of a neutral form.
 69. A process forproducing a pharmaceutical composition for delivering a supersaturatedconcentration of a drug having an aqueous solubility less than about 10mg/mL in gastric fluid conditions, which process comprises intimatelymixing together components: (a) a salt form of an API having an aqueoussolubility less than about 10 mg/mL in gastric fluid conditions; (b) aprecipitation retardant; and (c) an optional enhancer.
 70. The processfor producing a pharmaceutical composition according to claim 69,wherein the API is a sulfonamide.
 71. The process for producing apharmaceutical composition according to claim 69, wherein the API is abenzene sulfonamide.
 72. The process for producing a pharmaceuticalcomposition according to claim 69, wherein the API is celecoxib,deracoxib, valdecoxib, rofecoxib or eturicoxib.
 73. The process forproducing a pharmaceutical composition according to claim 69, whereinthe salt form of the API is an alkali metal or alkaline earth metalsalt.
 74. The process for producing a pharmaceutical compositionaccording to claim 69, wherein the salt form of the API is a sodium,potassium, lithium, or calcium salt.